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PMC:7376974 JSONTXT 18 Projects

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Id Subject Object Predicate Lexical cue
T1 0-45 Sentence denotes Hard Nanomaterials in Time of Viral Pandemics
T2 47-55 Sentence denotes Abstract
T3 56-159 Sentence denotes The SARS-Cov-2 pandemic has spread worldwide during 2020, setting up an uncertain start of this decade.
T4 160-367 Sentence denotes The measures to contain infection taken by many governments have been extremely severe by imposing home lockdown and industrial production shutdown, making this the biggest crisis since the second world war.
T5 368-500 Sentence denotes Additionally, the continuous colonization of wild natural lands may touch unknown virus reservoirs, causing the spread of epidemics.
T6 501-705 Sentence denotes Apart from SARS-Cov-2, the recent history has seen the spread of several viral pandemics such as H2N2 and H3N3 flu, HIV, and SARS, while MERS and Ebola viruses are considered still in a prepandemic phase.
T7 706-847 Sentence denotes Hard nanomaterials (HNMs) have been recently used as antimicrobial agents, potentially being next-generation drugs to fight viral infections.
T8 848-1010 Sentence denotes HNMs can block infection at early (disinfection, entrance inhibition) and middle (inside the host cells) stages and are also able to mitigate the immune response.
T9 1011-1081 Sentence denotes This review is focused on the application of HNMs as antiviral agents.
T10 1082-1255 Sentence denotes In particular, mechanisms of actions, biological outputs, and limitations for each HNM will be systematically presented and analyzed from a material chemistry point-of-view.
T11 1256-1346 Sentence denotes The antiviral activity will be discussed in the context of the different pandemic viruses.
T12 1347-1495 Sentence denotes We acknowledge that HNM antiviral research is still at its early stage, however, we believe that this field will rapidly blossom in the next period.
T13 1497-1596 Sentence denotes The current emergence caused by SARS-Cov-2 is dramatically changing the everyday life of all of us.
T14 1597-1729 Sentence denotes Due to the high globalization, new viruses can spread all over the world much faster than ever, infecting the communities worldwide.
T15 1730-1824 Sentence denotes The current technologies and measurements are able to sensibly slow down the infection spread.
T16 1825-1974 Sentence denotes However, their cost is tremendously high, impacting the healthcare systems and causing the shutdown of industries and the lockdown of the population.
T17 1975-2243 Sentence denotes The impact of SARS-Cov-2 on the worldwide economy is estimated to be a 2–3% decline, making this the biggest crisis since the world wars.1 A possible vaccine is hopefully expected to come in 1–2 years, originating a buffer period pretty much uncertain for many people.
T18 2244-2358 Sentence denotes Vaccination is the only way known to accelerate the flock immunity without causing further death by this pandemic.
T19 2359-2611 Sentence denotes Contemporary history has seen the spread of other viral pandemics such as H2N2 flu (1956–1958), H3N3 flu (1968), HIV (peak reached between 2005 and 2012), SARS (2009), while MERS (2012 to now) and Ebola (1975 to now) viruses are in a prepandemic phase.
T20 2612-2739 Sentence denotes The continuous colonization of wild nature lands may touch unknown virus reservoirs causing the spread of contagious epidemics.
T21 2740-3074 Sentence denotes Due to these facts, there is a clear urgency in the development of viral treatments to avoid the risk of new pandemics.2 In particular, the possibility to have smart antiviral tools able to efficiently disinfect surfaces, block the viral spreading, enhance the survival of infected people, and boost immunization are highly desirable.
T22 3075-3164 Sentence denotes In particular, more investments in the next years are expected in the antiviral research.
T23 3165-3780 Sentence denotes Hard nanomaterials (HNMs) have been extensively studied for many types of applications including drug delivery, bioimaging, and biosensing.3−5 The use of nanomaterials in biomedical research is highly developed, reaching in some cases clinical approval.6 Despite that, nanomaterials have been mainly developed for cancer therapy, while scarce attention has been spent on their application in viral infections.7 The continuous virology research has more and more increased into viral replication machinery, allowing the preparation and rationalization of more sophisticated vaccine formulations and viral inhibitors.
T24 3781-3917 Sentence denotes The use of HNMs may be one of the keys to provide more effective biomedical agents with a wide spectrum of activity in viral pandemics.8
T25 3918-4018 Sentence denotes An increasing number of reports describe how HNMs can be successfully applied to block viral spread.
T26 4019-4178 Sentence denotes HNMs can be used at different stages of viral infection: blocking viral entry, hampering interaction with infected host cells, and modulating immune responses.
T27 4179-4401 Sentence denotes Due to their core composition (e.g., metal oxides, noble metals), HNMs can have an important antiviral activity inactivating some specific proteins of the capsid or dysregulating radical homeostasis in the virus particles.
T28 4402-4564 Sentence denotes Additionally, surface functionalization can sensibly increase HNM antiviral activity, enabling the mimicking of host cells or enhancing the targeting efficiency.9
T29 4565-4677 Sentence denotes In this review, we will critically analyze different strategies for the application of HNMs as antiviral agents.
T30 4678-4786 Sentence denotes The rational and the synthetic strategies will be highlighted and correlated to different relevant examples.
T31 4787-4897 Sentence denotes Particular attention will be paid on the mechanisms of antiviral action and on HNM applicability and efficacy.
T32 4898-5061 Sentence denotes For the sake of clarity, this review is divided into three parts, namely: blocking viral entry, antiviral activity in host cells, and stimulation of immune system.
T33 5062-5115 Sentence denotes We have focused on the different stages of infection.
T34 5116-5300 Sentence denotes In the section dedicated to blocking viral entry, the application of HNMs for surface disinfection and inactivation of the virus prior to interaction with host cells will be described.
T35 5301-5520 Sentence denotes Subsequently, the interaction of HNMs after internalization into host cells will be addressed, stressing their antiviral delivery features and their activity in viral replication blockage, leading to host cell survival.
T36 5521-5662 Sentence denotes Then, activation of immune response induced by HNMs, triggering the innate and the adaptive (e.g., nanovaccines) immunity, will be presented.
T37 5663-5830 Sentence denotes The different adopted strategies will be correlated to the nanomaterial core (e.g., composition, size, shape) and surface (e.g., chemistry, surface charge) properties.
T38 5831-6086 Sentence denotes Finally, limits (e.g., unknown long-term toxicity), advantages (e.g., high and wide spectrum virucidal activity), and perspectives will be discussed with particular attention to the applications in viral pandemics (e.g., HIV, SARS, and influenza viruses).
T39 6087-6193 Sentence denotes This review is addressed to material and biomaterials scientists who are interested in antiviral research.
T40 6194-6358 Sentence denotes We acknowledge that application of HNMs as antiviral agents is still in the early stages; however, we believe that the research on this topic is going to grow soon.
T41 6359-6492 Sentence denotes Thus, with this contribution we genuinely hope to inspire researchers in the preparation of smart and efficient HNM antiviral agents.
T42 6494-6514 Sentence denotes Blocking Viral Entry
T43 6515-6595 Sentence denotes The last decades have been characterized by increasing investigation on viruses.
T44 6596-6774 Sentence denotes In particular, their surface charge, protein composition, and host cell entry mechanism have been elucidated, allowing to formulate the first-generation wide spectrum antivirals.
T45 6775-6894 Sentence denotes Blocking the viral entry is one of the most common known antimicrobial procedure to stop infections at the early stage.
T46 6895-7021 Sentence denotes In this context, antiviral materials have been used for surface disinfection or for epidemic limitation in humans and animals.
T47 7022-7187 Sentence denotes Due to their high surface to volume ratio, composition, and tunable surface chemistry, HNMs are now more and more studied as powerful agents in blocking viral entry.
T48 7188-7521 Sentence denotes As for other biological interactions, the attachment and entry of viruses into host cells are mediated by multivalent interactions between the surface of the virus and cell surface receptors.10 Nanomaterials can display multivalency that makes them able to compete with the host cells on virus attachment, limiting their infectivity.
T49 7522-7607 Sentence denotes The mechanism of antiviral actions relies on the inactivation of the capsid proteins.
T50 7608-7807 Sentence denotes As a matter of fact, HNMs have been used for: (1) blocking target proteins for viral entry, (2) capsid protein oxidation, (3) mimicking cell surface, and (4) mechanical rupture of viruses (Figure 1).
T51 7808-7960 Sentence denotes These strategies target proteins and mechanisms of entry common in most of the viruses, thus allowing the preparation of wide spectrum antiviral agents.
T52 7961-8068 Sentence denotes In this section, the application of different HNMs as powerful inhibitors of viral entry will be discussed.
T53 8069-8238 Sentence denotes Figure 1 Illustration of the main mechanisms of blocking virus entry into host cells: capsid denaturation, mimicking cell surface, and mechanical breaking of the virus.
T54 8240-8259 Sentence denotes Noble Nanoparticles
T55 8260-8440 Sentence denotes Noble nanoparticles (NPs), made of gold and silver, are attractive as antiviral agents for their surface functionalization versatility and their capacity to cleave disulfide bonds.
T56 8441-8527 Sentence denotes Their use in disinfection has been extensively studied for different types of viruses.
T57 8528-8684 Sentence denotes The morphology and the size of the NPs play a crucial role in their ability to efficiently interact with the capsids and in their toxicity for the organism.
T58 8685-8811 Sentence denotes These nanomaterials are characterized by a very large specific surface area (inversely proportional to the particle diameter).
T59 8812-8970 Sentence denotes As the particle size becomes smaller and smaller, the percentage of surface atoms increases, creating many unsaturated bonds due to lack of neighboring atoms.
T60 8971-9050 Sentence denotes As a consequence, AgNPs and AuNPs have unstable atoms with high surface energy.
T61 9051-9163 Sentence denotes This kind of structure provides a lot of contact adsorption sites and reaction points for further modifications.
T62 9164-9269 Sentence denotes These chemical features allow to easily combine surface NP atoms with other atoms through chemical bonds.
T63 9270-9401 Sentence denotes Besides the composition of the metal core, several studies have pointed out the importance of the control of the surface chemistry.
T64 9402-9551 Sentence denotes The surface groups can: (1) stabilize NPs in the biological media, (2) insert targeting agents, and (3) enhance the circulation time inside the body.
T65 9552-9731 Sentence denotes Antiviral efficiency can be also enhanced by the multivalency effect, where highly branched ligands are used to locally augment the local concentration of the targeting molecules.
T66 9732-9883 Sentence denotes In this section the main strategies and results for silver (AgNPs) and gold (AuNPs) nanoparticles in blocking viral entry will be critically discussed.
T67 9885-9905 Sentence denotes Silver Nanoparticles
T68 9906-10037 Sentence denotes Many studies have shown that naked AgNPs have a good effect on the control and prevention of a variety of viral diseases (Table 1).
T69 10038-10102 Sentence denotes However, the antiviral mechanism of nanosilver is still unclear.
T70 10103-10168 Sentence denotes The antiviral action is associated with the following mechanisms:
T71 10169-10349 Sentence denotes Nanosilver can prevent the virus from entering the host cells and inhibit the virus from binding to the cell receptor, thereby stopping the virus from infecting the targeted cells.
T72 10350-10497 Sentence denotes AgNPs may be able to bind the viral surface protein and inhibit the interaction between the virus and the cell membrane receptors (Figure 2, left).
T73 10498-10722 Sentence denotes However, it has been also reported that AgNPs can inactivate the virus through denaturation of surface proteins containing cysteine and methionine residues present on the viral capsid, in a similar way reported for bacteria.
T74 10723-11170 Sentence denotes For example, AgNPs smaller than 10 nm were shown to interact with the sulfur-bearing residues of gp120 glycoprotein knobs distributed on the lipid membrane of HIV-1 virus, preventing the virus from binding to CD4 receptor site on the host cells, thus inhibiting the viral infection.11 By means of a viral adsorption assay, it was shown that the AgNP mechanism of anti-HIV action is based on the inhibition of the initial stages of the HIV-1 cycle.
T75 11171-11423 Sentence denotes To demonstrate that the antiviral effect of AgNPs is due to the particle structure rather than to silver ions present in solution, the antiviral activity of silver sulfadiazine (AgSD) and silver nitrate (known antibacterial silver salts) was evaluated.
T76 11424-11814 Sentence denotes Both salts showed a much lower therapeutic index than AgNPs in vitro, indicating that silver ions themselves are less efficient.12 These results point out that the antiviral efficacy is not only related to the dose of Ag+ ions present in solution but is also regulated by different other parameters (e.g., size, charge, and surface functionalization) associated with the nanosize dimension.
T77 11815-12164 Sentence denotes For instance, in the case of Herpesviridae and Paramyxoviridae viruses (both enveloped viruses with embedded viral-encoded glycoproteins), AgNPs can effectively reduce their infectivity, by blocking the interaction between the viral particles and the host cells with an antiviral activity strictly dependent on the size and ζ potential of the AgNPs.
T78 12165-12263 Sentence denotes As a general observation, it was reported that smaller nanoparticles have better antiviral effect.
T79 12264-12660 Sentence denotes This effect was associated with the increase of the surface area, where smaller-sized AgNPs could bind more efficiently to the viral particles exerting a higher antiviral activity.13 Another study reported the impairment of Peste des petits ruminants virus (PPRV) replication after incubating infectious viral particles with AgNPs, which did not exhibit any virucidal effect even up to 900 μg/mL.
T80 12661-12797 Sentence denotes This result suggested that the anti-PPRV activity of the AgNPs is due to the inhibitory effect on viral replication in the target cells.
T81 12798-12904 Sentence denotes AgNPs do not prevent the binding of PPRV to host cells, but inhibit the entry of viruses into these cells.
T82 12905-13073 Sentence denotes AgNPs can also interact with the surface and core of PPRV, but this interaction cannot kill the virus directly.12 The same results were then confirmed on other viruses.
T83 13074-13184 Sentence denotes AgNPs with a diameter of 25 nm inhibited Vaccinia virus replication by preventing viral entry into host cells.
T84 13185-13351 Sentence denotes However, AgNPs cannot prevent the virus from adsorbing onto the cells, and this virus is still infectious, indicating that AgNPs lack a direct virus-killing effect.13
T85 13352-13787 Sentence denotes Figure 2 Potential antiviral mechanism of AgNPs. (1) AgNPs interact with viral envelope and/or viral surface proteins; (2) AgNPs interact with cell membranes and block viral penetration; (3) AgNPs block cellular pathways of viral entry; (4) AgNPs interact with viral genome; (5) AgNPs interact with viral factors necessary for viral replication; and (6) AgNPs interact with cellular factors necessary for productive viral replication.
T86 13788-13829 Sentence denotes Reproduced with permission from ref (14).
T87 13830-13864 Sentence denotes Copyright 2016 Taylor and Francis.
T88 13865-13929 Sentence denotes Table 1 Antiviral AgNPs and Their Possible Mechanisms of Action
T89 13930-14001 Sentence denotes virus shape size (nm) active concentration mechanism of action ref
T90 14002-14064 Sentence denotes HIV-1 spherical 1–10 25 μg/mL interaction with gp120 (11)
T91 14065-14126 Sentence denotes HIV-1 IIIB – 30–50 440 μg/mL interaction with gp120 (19)
T92 14127-14252 Sentence denotes HSV-1, HSV-2, and HPIV-3 – 20–50 not available possible interaction directly with the viral envelope or its protein (20)
T93 14253-14360 Sentence denotes Adenovirus type 3 spherical 5–18 25 μg/mL direct destruction of virus particles and DNA structure (15)
T94 14361-14522 Sentence denotes H1N1 influenza A virus spherical 5–20 12.5 μg/mL inhibition of respiratory enzymes and electron transport components and interference with DNA function (21)
T95 14523-14630 Sentence denotes HBV spherical 10–50 5 μM interaction with double-stranded DNA and/or binding with viral particles (16)
T96 14631-14711 Sentence denotes PPRV spherical 5–30 11.1 μg/mL interaction with virus surface and core (12)
T97 14712-14802 Sentence denotes Vaccinia virus spherical 25 not available preventing viral entry into host cells (13)
T98 14803-14903 Sentence denotes Monkey pox virus (MPV) – 10–80 12.5 μg/mL blocking virus-host cell binding and penetration (22)
T99 14904-14996 Sentence denotes Tacaribe virus (TCRV) – 5–10 25 μg/mL inactivation of virus particles before entry (23)
T100 14997-15108 Sentence denotes Poliovirus spherical 4–9 3.1 ppm preventing viral particles from binding to the receptors of RD cells (24)
T101 15109-15222 Sentence denotes TGEV spherical <20 12.5 μg/mL direct interaction with TGEV surface protein, such as TGEV S glycoprotein (18)
T102 15223-15242 Sentence denotes linear 60000–80000
T103 15243-15440 Sentence denotes linear 20000–30000 Alternatively, nanosilver can be combined with viral nucleic acids to change the capsid structure, affect the replication of viral genetic material, and make the virus inactive.
T104 15441-15876 Sentence denotes For example, TEM analyses have shown that NPs can cause a change of the structure of the Ad3 virus from a hexahedral shape to an irregular shape, destroying its fibers and capsid proteins, leading to inhibition of the virus from binding to the host cells and destroying the DNA structure, preventing adenoviral infection.15 Nanosilver can also bind directly to the double-stranded DNA of hepatitis B virus to inhibit its replication.16
T105 15877-15994 Sentence denotes In other studies, it has been demonstrated that silver ions released from nanosilver can directly damage the viruses.
T106 15995-16064 Sentence denotes Based in this property, an interesting application has been proposed.
T107 16065-16193 Sentence denotes AgNPs were used as a coating on polyurethane condoms, effectively inhibiting the activity of HIV and herpes simplex virus (HSV).
T108 16194-16354 Sentence denotes The hypothesized mechanism is that silver ions are transferred directly from oxidized NPs to biological targets, such as viral membrane proteins gp120 and gp41.
T109 16355-16478 Sentence denotes In addition, a small amount of silver ion is also released from the coated contraceptives to improve the antiviral level.17
T110 16479-16705 Sentence denotes Although the studies on naked AgNPs to reduce viral infectivity have shown their potential as broad-spectrum antiviral agents, the understanding of the specific antiviral action mechanism still needs to be elucidated in depth.
T111 16706-16991 Sentence denotes Many studies have shown that the antiviral performance of naked AgNPs is related to their size, and smaller nanoparticles have better antiviral activities.16 In addition to particle size, the antiviral action of AgNP morphology has also attracted interest to fight against coronavirus.
T112 16992-17187 Sentence denotes AgNPs and two types of silver nanowires were able to significantly cause an inhibitory effect on coronavirus transmissible gastroenteritis (TGEV)-induced host cell infection and TGEV replication.
T113 17188-17349 Sentence denotes The mechanism is likely based on a direct interaction of AgNPs with TGEV surface proteins (e.g., TGEV glycoproteins) to inhibit the beginning of viral infection.
T114 17350-17526 Sentence denotes It is possible that AgNPs and Ag nanowires alter the structure of some surface proteins of TGEV and then inhibit their recognition and adhesion to the cellular receptor pAPN.18
T115 17527-17732 Sentence denotes Although the potential of AgNPs as antiviral agents has been commonly recognized, unfortunately, their wide biological applications are limited by the risks of self-aggregation and environmental pollution.
T116 17733-17963 Sentence denotes Silver ions can be released from the surface of AgNPs and potentially pollute the environment, and their agglomeration into bulkier particles or fibers may change their biological characteristics, diminishing the antiviral effect.
T117 17964-18218 Sentence denotes In several cases, it has been reported that naked AgNPs may affect human health.25 Therefore, research and development of AgNPs whose surface is modified or stabilized by protecting molecular layers is an urgent need to overcome these problems (Table 2).
T118 18219-18299 Sentence denotes Poly(N-vinyl-2-pyrrolidone) (PVP) is the most commonly used stabilizer of AgNPs.
T119 18300-18905 Sentence denotes The PVP-coated AgNPs are able to inhibit the activities of HIV-1, herpes simplex 2 virus (HSV-2), and respiratory syncytial virus (RSV).11,26,27 But compared to foamy carbon, small-sized PVP and BSA-coated AgNPs showed poor antiviral activity to the HIV-1 virus.11 For RSV, PVP-coated AgNPs have a specific binding capacity to the viral surface, evidencing a regular spatial arrangement and a clear interaction with G-protein.26 In addition, to improve the stability of AgNPs, their surface modification with antiviral drugs was proved to reduce the drug resistance caused by the drugs administered alone.
T120 18906-19003 Sentence denotes Tannic acid-modified AgNPs showed good antiviral effects on HSV-2 infection in vitro and in vivo.
T121 19004-19097 Sentence denotes The viral infection was inhibited only when these NPs directly interacted with HSV-2 virions.
T122 19098-19184 Sentence denotes Indeed, the pretreatment of host cells with such AgNPs did inhibit the entry of HSV-2.
T123 19185-19422 Sentence denotes Due to the high affinity of tannins to proteins and sugars, tannic acid can bind glycoproteins on the surface of viruses to make them inert, impairing glycoprotein function and preventing viruses from attaching and entering host cells.28
T124 19423-19498 Sentence denotes Table 2 Surface-Modified Antiviral AgNPs and Possible Mechanisms of Action
T125 19499-19557 Sentence denotes virus shape size (nm) coating mechanism of action ref
T126 19558-19637 Sentence denotes HIV-1 spherical 1–10 foamy carbon, PVP and BSA interaction with gp120 (11)
T127 19638-19760 Sentence denotes RSV spherical – PVP, BSA, and recombinant F protein (RF 412) interaction with the G-protein on the virus surface (26)
T128 19761-19879 Sentence denotes H1N1 influenza virus spherical 2–5 Oseltamivir inhibition of the activity of neuraminidase and hemagglutinin (34)
T129 19880-19896 Sentence denotes Amantadine (35)
T130 19897-19912 Sentence denotes Zanamivir (36)
T131 19913-19978 Sentence denotes inhibition of accumulation of reactive oxygen species (ROS)    
T132 19979-20094 Sentence denotes HAV, NoV and CoxB4 spherical – polyphosphonium-oligochitosans preventing viral attachment and penetration (29)
T133 20095-20188 Sentence denotes MPV spherical 10–80 polysaccharide blocking virus-host cell binding and penetration (22)
T134 20189-20278 Sentence denotes TCRV spherical 10 polysaccharide inactivation of virus particles prior to entry (23)
T135 20279-20383 Sentence denotes HSV-1 spherical 4 mercaptoethanesulfonate competition for the binding of the virus to the cell (30)
T136 20384-20521 Sentence denotes Enterovirus 71 (EV71) spherical 2–5 PEI and antiviral siRNA inhibition of the accumulation of ROS and activation of AKT and p53 (37)
T137 20522-20718 Sentence denotes HSV-2 spherical 13, 33, 46 tannic acid direct interaction and blocking of virus attachment, penetration and spread (28) The surface modification can also exert a synergistic antiviral effect.
T138 20719-20857 Sentence denotes AgNPs decorated with polyphosphonium-oligochitosan (PQPOC) exhibited moderate to excellent antiviral activity against HAV, NoV, and CoxB4.
T139 20858-20967 Sentence denotes In addition, AgNPs could interact with the virion glycoproteins and prevent viral attachment and penetration.
T140 20968-21209 Sentence denotes PQPOC can also serve as an effective virus inhibitor by blocking the interaction of the targeted virus with the host through the electrostatic interaction between the cationic polymers and the negatively charged binding sites of the virus.29
T141 21210-21306 Sentence denotes Surface-modified AgNPs can also prevent viral infection by competitive adsorption on host cells.
T142 21307-21483 Sentence denotes The process of infection of cells by herpes simplex virus type 1 (HSV-1) involves the interaction between viral envelope glycoproteins and heparan sulfate (HS) on cell surface.
T143 21484-21686 Sentence denotes Therefore, researchers designed AgNPs capped with mercaptoethanesulfonate (Ag-MES) to compete with the cellular HS through the sulfonate end groups, thereby blocking the virus from entering the cells.30
T144 21687-22193 Sentence denotes A few years ago, it was shown that curcumin could prevent the replication and the budding of RSV,31 but the disadvantage of poor solubility and low bioavailability limited its clinical application.32 Curcumin was used as a reducing and capping agent to prepare stable curcumin AgNPs (cAgNPs) under physiological conditions. cAgNPs could reduce cytopathic effects induced by RSV and showed efficient antiviral activity against infection by directly inactivating the virus prior to entry into the host cells.
T145 22194-22279 Sentence denotes Its antiviral effect was higher than curcumin alone or unmodified AgNPs (Figure 3).33
T146 22280-22413 Sentence denotes Figure 3 Schematic representation of the synthesis of cAgNPs (A) and a proposed inhibition mode of cAgNPs against RSV infection (B).
T147 22414-22592 Sentence denotes The inhibition mode of (B) shows that cAgNPs can reduce the binding ability of virus with the binding centers on the surface of cells (b) as compared to those without cAgNPs (a).
T148 22593-22634 Sentence denotes Reproduced with permission from ref (33).
T149 22635-22674 Sentence denotes Copyright 2016 Royal Chemistry Society.
T150 22675-22832 Sentence denotes Alternatively, Zhu et al. prepared AgNPs surface-modified with oseltamivir, amantadine, and zanamivir (Ag@OTV,34 Ag@AM,35 and Ag@ZNV36), by chemical methods.
T151 22833-22953 Sentence denotes The results showed that these nanoparticles can directly interact with the virions, resulting in viral function damages.
T152 22954-23037 Sentence denotes Overall different studies have reported the capacity of AgNPs to block viral entry.
T153 23038-23236 Sentence denotes However, there is not a concerted antiviral mechanism, but their activity differs from case to case, based on viral particle adsorption, capsid structure alteration, or surface protein denaturation.
T154 23237-23467 Sentence denotes For AgNPs, the antiviral activity can be associated with different parameters including size, shape, surface charge, and functionalization but also to the topical release of silver ions able to disturb the viral cycle replication.
T155 23468-23645 Sentence denotes As described before, bare AgNPs can be used as disinfectant agents, however their use in biological media is limited by their low colloidal stability and potential cytotoxicity.
T156 23646-23830 Sentence denotes Surface functionalization can alleviate cytotoxicity, but it can also mask the nanoparticle surface, reducing their affinity for viral particles, thus reducing AgNP antiviral activity.
T157 23831-23956 Sentence denotes For these reasons, AgNPs at the moment could find application mainly for surface disinfection and for topical administration.
T158 23957-24047 Sentence denotes Further studies are needed to prepare safer AgNP formulations for systemic administration.
T159 24048-24301 Sentence denotes In particular, the clarification of the antiviral mechanisms and the use of surface functional groups able to stabilize AgNPs in biological fluids without affecting their prominent antiviral activity are probably the most important challenges to tackle.
T160 24303-24321 Sentence denotes Gold Nanoparticles
T161 24322-24552 Sentence denotes Compared to AgNPs, AuNPs exhibit reduced toxicity on healthy cells, making them more attractive for in vivo and clinical applications.38 Indeed, AuNPs have been successfully tested as inhibitors of viral entry into the host cells.
T162 24553-24750 Sentence denotes AuNPs interact with hemagglutinin (HA), where Au is able to oxidize the disulfide bond of this glycoprotein causing its inactivation, thus impeding the membrane fusion of the virus with host cells.
T163 24751-25212 Sentence denotes Targeting HA has emerged as an alternative strategy to the actual therapies (e.g., matrix protein 2 and neuramidase), especially to pandemic viruses that show an accelerated mutation speed of their surface proteins, hence a resistance to conventional treatments increasing their infectivity and mortality.38 This strategy has been applied to influenza (e.g., H1N1, HCV) and herpes viruses.39−44 The activity of AuNPs is proportional to the surface area exposed.
T164 25213-25330 Sentence denotes As a consequence, the size and the morphology of these metal NPs play a substantial role in their antiviral activity.
T165 25331-25649 Sentence denotes Recently, Kim et al. have reported that porous AuNPs are able to inhibit influenza A infection more efficiently than nonporous AuNPs.39 This effect has been associated with the higher surface area of the porous material that favors their interaction with capsids and thus increases their antiviral activity (Figure 4).
T166 25650-25759 Sentence denotes Figure 4 Schematic illustration of inactivation of influenza A virus (IAV) treated with porous AuNP (PoGNP).
T167 25760-25836 Sentence denotes PoGNP interacts with IAV surface proteins and cleaves their disulfide bonds.
T168 25837-25892 Sentence denotes Inactivated viruses exhibit lower infectivity to cells.
T169 25893-25973 Sentence denotes Reproduced with permission under a Creative Commons CC-BY license from ref (39).
T170 25974-26026 Sentence denotes Copyright 2020 BioMed Central Ltd., Springer Nature.
T171 26027-26168 Sentence denotes Besides the per se antiviral activity, AuNP surface modifications have been developed in order to enhance their overall therapeutic benefits.
T172 26169-26287 Sentence denotes The engineering of tailored AuNPs with selected ligands has allowed the preparation of efficient antiviral nanoagents.
T173 26288-26418 Sentence denotes The target ligands can be introduced directly during the particle synthesis via ligand exchange reactions or ligand modifications.
T174 26419-26906 Sentence denotes For instance, direct reduction of gold ions in the presence of gallic acid produced homogeneous AuNPs able to sensibly reduce herpes simplex virus infection in vitro.40 Compared to free ligand NPs, functionalized AuNPs benefit from the multivalency effect and higher circulation times, decreasing the needed therapeutic concentrations.39 Functionalized AuNPs can present organic groups that mimic host cell surfaces or other specific molecular patterns that selectively target the virus.
T175 26907-27029 Sentence denotes Normally, negative charges are used to mimic cell surfaces and favor the interaction between the particles and the capsid.
T176 27030-27521 Sentence denotes In particular, sulfonates and organic sulfates have been used for their capacity to attract the virus via capsid protein interaction and block the HA activity.41 AuNPs functionalized with sulfonates showed an increasing inhibition of influenza A compared to the nanoparticles capped with succinic acid.42 This study also demonstrated that there is not a correlation between the negative charge and the antiviral activity, but instead the inhibition depends mainly on the organic groups used.
T177 27522-27710 Sentence denotes Thiol-capped AuNPs also displayed powerful inactivation of bovine viral diarrhea virus in vitro.43 Multivalency has been exploited in more complex systems using dendrons as capping agents.
T178 27711-27893 Sentence denotes This strategy allows to generate higher concentrations of the target ligand in close proximity to the AuNPs and to increase the binding efficiency of the nanoparticles to the capsid.
T179 27894-28010 Sentence denotes The driving force of the antiviral efficiency relies on the concentration of the targeting agent onto the particles.
T180 28011-28188 Sentence denotes Sulfonated dendrons were grafted to AuNPs via a sulfide bond and tested for HIV inhibition.44 The results showed that the decorated AuNPs exerted a higher affinity to the virus.
T181 28189-28429 Sentence denotes Additionally, comparing AuNPs functionalized with different generation dendrons, those with a third generation displayed the highest inhibition performance with an IC50 below 0.1 μmol/mL, thus making them attractive for in vivo translation.
T182 28430-28896 Sentence denotes It is worth noting that the inhibition efficiency is strictly dependent on the available sulfonate groups present on the surface of the NPs, making crucial a thorough characterization of the material.44 The size of the AuNPs clearly plays an important role in the concentration of targeting ligands exposed per particle.45 Indeed, too big NPs have a limited surface area, while too small would not allow an efficient grafting of the dendrons due to steric hindrance.
T183 28897-29095 Sentence denotes For instance, it has been shown that dendron-functionalized AuNPs showed a size-dependent antiviral activity for influenza virus, where 14 nm particles exhibited a higher efficiency than 2 nm AuNPs.
T184 29096-29272 Sentence denotes This has been associated with the low functionalization grade of the small nanoparticles and to the inappropriate spatial distribution of the interacting ligand/receptor pairs.
T185 29273-29378 Sentence denotes The development of viral proteomics has profoundly transformed the antiviral and disinfection strategies.
T186 29379-29500 Sentence denotes In particular, small molecules and peptides able to target and block the viral biochemical machinery have been developed.
T187 29501-29682 Sentence denotes However, despite these efforts into the drug design, many of these molecules suffer from poor biological effect, low concentration in the diseased areas, and undesired side effects.
T188 29683-29825 Sentence denotes In this context, AuNPs have been coupled to biologically inactive small molecules to create biologically active multivalent AuNP therapeutics.
T189 29826-30124 Sentence denotes A bright example has been reported by Bowman et al., where the authors functionalized AuNPs with SDC-1721, a small membrane fusion inhibitor of HIV.46 The results demonstrated that, while pure SDC-1721 has low activity, functionalized AuNPs are able to inhibit HIV replication at μM concentrations.
T190 30125-30185 Sentence denotes Similar results have been reported using targeting peptides.
T191 30186-30401 Sentence denotes In particular, it was evidenced that the functionalized AuNPs can sensibly reduce the IC50 up to 2 orders of magnitude compared to pure peptides.47 Preliminary results in vivo confirmed the biosafety of the AuNPs.48
T192 30403-30451 Sentence denotes Nanoparticles Generating Reactive Oxygen Species
T193 30452-30642 Sentence denotes One of the main advantages of using NPs compared to oxidized metals relies on the slow release of ions and clusters from these particles, leading to an enhancement of the antiviral activity.
T194 30643-30877 Sentence denotes Additionally, the use of metal NPs containing Cu or Fe in ionic form catalyzes the generation of radicals via Fenton and Fenton-like reactions oxidizing the capsid proteins and consequently blocking the viral infection at early stage.
T195 30878-31580 Sentence denotes For instance, copper ions (derived from sulfates or iodide salts) have been widely used as antiviral agents because of their activity on several kinds of enveloped and non-enveloped viruses including influenza virus,49−51 herpes simplex virus52−54 and hepatitis A virus.55 Their mechanism of action relies on the formation of Cu+ ions (from soluble salts or nanoparticles) that generate hydroxyl radicals.56 The use of metallic copper nanostructures in the form of particles or sheets has shown only a moderate efficiency due to the low concentration and low release of Cu+.56 For these reasons, Cu+ salts, where the copper ions are readily present in their active monocationic form, have been favored.
T196 31581-32107 Sentence denotes In particular, CuI nanoparticles (stable at room temperature) have been extensively studied for deactivation of feline calicivirus56 and H1N1 pandemic influenza virus.57 However, the use of copper salts at high concentrations can irreversibly alter reactive oxygen species (ROS) homeostasis of healthy cells, provoking a general toxicity for the organism, limiting their applications to disinfection.56 Nanostructured cuprous and cupric oxides have been also extensively employed as antiviral agents for in vitro applications.
T197 32108-32317 Sentence denotes For instance, cuprous oxide nanoparticles (CuONPs) were successfully employed against hepatitis C.58 In particular, it was found that these NPs exerted a favorable antiviral activity with no cytotoxic effects.
T198 32318-32406 Sentence denotes CuONPs target the binding and entry step of viral infection to hepatic cells (Figure 5).
T199 32407-32545 Sentence denotes Similar results were reported on the use of CuONPs against HSV-1, however without any profound investigation on the antiviral mechanism.59
T200 32546-32688 Sentence denotes Figure 5 Huh7.5.1 cells at 72 h post-infection were stained with HCV-positive serum from patients (green signal) and with DAPI (blue signal).
T201 32689-32760 Sentence denotes Cuprous oxide NPs (CuONPs) are able to reduce viral infection in vitro.
T202 32761-32802 Sentence denotes Reproduced with permission from ref (58).
T203 32803-32831 Sentence denotes Copyright 2015 Elsevier B.V.
T204 32832-33052 Sentence denotes Alternatively, zinc salts have been successfully used as antimicrobial agents from research up to clinical trials for viral warts.60,61 More recently, ZnO nanoparticles (ZnONPs) were developed for the treatment of HSV-2.
T205 33053-33208 Sentence denotes ZnONPs were prepared with a tetrapod morphology.62 The results showed that they can mimic cell surface interacting with the HS present on the viral capsid.
T206 33209-33462 Sentence denotes Additionally, these particles have been used for photocatalysis showing to efficiently destroy the viral proteins upon UV irradiation.62 Besides all these interesting examples, in vivo applications are still needed to validate this therapeutic modality.
T207 33463-33569 Sentence denotes Due to the generation of high levels of ROS, the toxicity of copper nanoparticles has been widely debated.
T208 33570-33817 Sentence denotes The antiviral activity of copper nanoparticles is generally associated with the release of Cu+ ions in solution, thus the leakage of cytotoxic cationic species can be modulated by surface functionalization before in vitro and in vivo applications.
T209 33818-33930 Sentence denotes On the other side, the use of nanomaterials generating ROS can find applications in textile and surface coating.
T210 33931-34126 Sentence denotes The general broad virucidal efficiency of copper oxide nanoparticles shown for H1N1 pandemic influenza57 should be tested on SARS-Cov-2 and might be used for improving mask protection efficiency.
T211 34128-34148 Sentence denotes Carbon Nanomaterials
T212 34149-34293 Sentence denotes Due to their diversity, versatility, and tunable surface chemistry, carbon nanomaterials have been attractive for several types of applications.
T213 34294-34436 Sentence denotes In particular, the past decade has seen a tremendous raise in the preparation of performant carbon-based nanomaterials in the antiviral field.
T214 34437-34538 Sentence denotes Fullerene and its derivatives are the most studied carbon nanomaterials for their virucidal activity.
T215 34539-34672 Sentence denotes Due to the lack of solubility of pristine fullerene, functionalization strategies have been developed to prepare water-soluble drugs.
T216 34673-34951 Sentence denotes Investigations in the biomedical field evidenced the membranotropic capacity of fullerene derivatives.63 By modulating shape and functions, fullerene derivatives have been shown to possess antiviral properties through inhibition of viral entry and blockage of viral replication.
T217 34952-35039 Sentence denotes From these results, the attention has been directed also to other carbon nanomaterials.
T218 35040-35186 Sentence denotes In particular, functional carbon dots (CDs) and graphene oxide (GO) have been investigated for their ability to block viral entry into host cells.
T219 35188-35203 Sentence denotes Glycofullerenes
T220 35204-35383 Sentence denotes The emerging of mortal viruses, like Ebola or Zika, and the lack of suitable treatments led the academic and the industrial communities to look for alternative therapeutic routes.
T221 35384-35547 Sentence denotes Most of these pathogens are RNA enveloped viruses, and they share common infection mechanisms that can be targeted for the preparation of wide spectrum antivirals.
T222 35548-35802 Sentence denotes The external surface of the envelope of these viruses is covered by glycans that tightly interact with lectin receptors on host cells.64 This strong interaction allows the attachment of the virions to the cells, followed by internalization and infection.
T223 35803-35898 Sentence denotes Blocking lectin receptors is a general strategy used to stop viral infection at an early stage.
T224 35899-36149 Sentence denotes Fullerenes have been widely investigated as antiviral molecules, drug carriers, or tissue scaffolds.65 Fullerene applications have been recently extended to the design of mannosylated derivatives to block the entry of viral particles into host cells.
T225 36150-36270 Sentence denotes Mannose, due to the high affinity with lectin receptors, competes with the virus in the interaction with the host cells.
T226 36271-36445 Sentence denotes For example, one of the targets is the inhibition of viral particles through the interaction of mannose with the dendritic cell-specific ICAM-grabbing non-integrin (DC-sign).
T227 36446-36706 Sentence denotes DC-sign receptors mediate the interactions between DCs and T cells.66,67 To exploit these characteristics, mannose was combined with fullerene in the design of the so-called glycofullerenes to study their capacity to inhibit Ebola, Dengue, and other pathogens.
T228 36707-37241 Sentence denotes For this purpose, different glycofullerenes were synthesized by changing the number of mannose units (from 12 to 36) and the spacers between the fullerene moieties and by varying steric hindrance in order to obtain a library of molecules.66 The synthetic route is composed of three steps based on “click chemistry”: (1) assembly of glycodendrons by Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC), (2) synthesis of alkyne-substituted Bingel-Hirsch hexakis-adducts, and (3) the coupling between the last two products again by CuAAC.
T229 37242-37373 Sentence denotes To increase the number of mannose moieties up to 36, the glycodendron core was changed from malonate to trialkynyl pentaerythritol.
T230 37374-37453 Sentence denotes In order to compare the different derivatives, in vitro studies were performed.
T231 37454-37638 Sentence denotes Jurkat cells (lymphocyte T CD4 immortalized cells) expressing DC-sign were used to prove the inhibition capacity of the glycofullerenes on viral infection of Ebola (Figure 6, route A).
T232 37639-37946 Sentence denotes The study revealed an IC50 in the μM range for the 12 mannose fullerene, a lower efficiency with the 36 mannose fullerene with a short spacer (PEG, with 2 ethylene oxide units), while a nanomolar IC50 was achieved with 36 mannose fullerenes with a longer spacer (PEG, with 3 ethylene oxide units) (Table 3).
T233 37947-38115 Sentence denotes This first proof-of-concept study was then expanded, aiming to obtain a better antiviral activity by increasing the valence and inserting longer and flexible spacers.68
T234 38116-38205 Sentence denotes Figure 6 Chemical design and general scheme to block the viral entry by glycofullerenes.
T235 38206-38508 Sentence denotes Three different shapes of glycofullerenes can act as inhibitor of viral infection: (A) shape composed of monodisperse fullerene bearing mannose, (B) assembly as “sugar balls” of tridecafullerenes exhibiting mannose on the edges, and (C) supramolecular micellar aggregates of fullerenes bearing mannose.
T236 38509-38588 Sentence denotes Table 3 Antiviral Activity of Different Fullerenes Functionalized with Mannose
T237 38589-38724 Sentence denotes material functional groups core function number of mannose moieties virus number of atoms between fullerene and mannose IC50 ref
T238 38725-38791 Sentence denotes glycofullerene monosaccharide malonate 12 Ebola 8 2 μM (66)
T239 38792-38872 Sentence denotes glycofullerene monosaccharide trialkynyl pentaerythritol 36 Ebola 22 68 μM
T240 38873-38954 Sentence denotes glycofullerene monosaccharide trialkynyl pentaerythritol 36 Ebola 28 0.3 μM
T241 38955-39032 Sentence denotes trideca-fullerenesa monosaccharide malonate 120 Ebola 8 20.375 nM (69)
T242 39033-39103 Sentence denotes trideca-fullerenesb monosaccharide malonate 120 Ebola 8 0.667 nM
T243 39104-39189 Sentence denotes glycofullerene disaccharide trialkynyl pentaerythritol 36 Zika 29 8.35 nM (70)
T244 39190-39205 Sentence denotes Dengue 7.71 nM
T245 39206-39290 Sentence denotes trideca-fullerenes disaccharide trialkynyl pentaerythritol 120 Zika 29 0.52 nM
T246 39291-39307 Sentence denotes Dengue 0.098 nM
T247 39308-39393 Sentence denotes trideca-fullerenes disaccharide trialkynyl pentaerythritol 360 Zika 48 0.067 nM
T248 39394-39410 Sentence denotes Dengue 0.035 nM
T249 39411-39507 Sentence denotes micellar glycofullerenes monosaccharide trialkynyl pentaerythritol 6 Ebola 23 424 nM (72)
T250 39508-39599 Sentence denotes micellar glycofullerenes monosaccharide trialkynyl pentaerythritol 12 Ebola 25 196 nM
T251 39600-39660 Sentence denotes a Small spacer between core C60 and surrounding fullerenes.
T252 39661-39721 Sentence denotes b Large spacer between core C60 and surrounding fullerenes.
T253 39722-39814 Sentence denotes Based on these studies, another class of multivalent fullerene dendrimers was then designed.
T254 39815-39958 Sentence denotes A fast and controlled synthetic route was developed to achieve giant globular multivalent fullerenes, containing hundreds of functional groups.
T255 39959-40136 Sentence denotes The first study was performed with tridecafullerenes containing 120 mannoses.69 The molecular structure is composed of 12 hexakis C60 surrounding a C60 core (Figure 6, route B).
T256 40137-40441 Sentence denotes Compared to the previous study, an IC50 3 orders of magnitude lower was measured on the inhibition of Ebola virus (Table 3).66,68 In order to present more carbohydrates at the periphery of the dendrimer, a trialkynyl pentaerythritol derivative allowed to afford a tridecafullerene with 360 carbohydrates.
T257 40442-40864 Sentence denotes In this case, the molecule was synthesized with a C60 tridecafullerene bearing α(1,2)mannobioside.70 The use of this disaccharide was already investigated, showing an increase of affinity with DC-sign receptors by a factor of 3–4.71 The synthetic strategy exploited also the use of strain-promoted copper-free cycloaddition of azides to alkynes (SPAAC) for the coupling of the core fullerene to the surrounding fullerenes.
T258 40865-40947 Sentence denotes SPAAC allows an easier purification avoiding the removal of cytotoxic copper ions.
T259 40948-41059 Sentence denotes The inhibition performance of this molecule was studied in vitro with viral pseudoparticles of Dengue and Zika.
T260 41060-41170 Sentence denotes The comparison was made between 360 and 120 disaccharides tridecafullerenes and 36 disaccharide monofullerene.
T261 41171-41304 Sentence denotes The results highlighted a picomolar IC50 inhibition on both Zika and Dengue models for the 360 disaccharide glycofullerene (Table 3).
T262 41305-41419 Sentence denotes The ability to inhibit other types of viruses allows the use of glycofullerenes as broad spectrum antiviral drugs.
T263 41420-41516 Sentence denotes Moreover, the negligible toxicity to other cells proved the biocompatibility of these molecules.
T264 41517-41749 Sentence denotes Following an alternative strategy, a supramolecular assembly of monodisperse glycofullerenes, leading to the formation of micelles, was achieved and tested.72 These micelles present a uniform and spherical shape (Figure 6, route C).
T265 41750-41954 Sentence denotes The aggregation synthetic route is faster compared to a controlled synthesis of giant glycofullerenes, but it might suffer from low reproducibility and batch-to-batch differences between each formulation.
T266 41955-42218 Sentence denotes This self-assembled C60 functionalized with 6 or 12 mannoses exposes a large amount of carbohydrate at the surface, leading to an inhibition of Ebola virus in the nanomolar range (IC50 of 424 nM for six mannoses and 196 nM for 12 mannoses, respectively, Table 3).
T267 42219-42309 Sentence denotes Further in vitro studies evidenced again a good biocompatibility of these glycofullerenes.
T268 42310-42447 Sentence denotes While there are no in vivo studies yet, these promising results enlarge the panel of molecules in the fight against new emerging viruses.
T269 42448-42578 Sentence denotes Functionalized fullerenes have been used for their ability to compete with viral particles through lectin receptors in host cells.
T270 42579-42819 Sentence denotes There has been a tremendous advancement in the functionalization of fullerenes leading to the preparation of derivatives with a high amount of mannose, capable to enhance the multivalency effect and thus to increase the therapeutic outcome.
T271 42820-42887 Sentence denotes First, glycofullerenes do not have an intrinsic virucidal activity.
T272 42888-42978 Sentence denotes They can reduce the infectivity, but they are not able to completely inactivate the virus.
T273 42979-43103 Sentence denotes Second, the mechanism of action of glycofullerenes relies on their interaction with host cells and not with viral particles.
T274 43104-43307 Sentence denotes Thus, for a therapeutic application, they should be injected at different time points, ensuring that the local concentration is therapeutically relevant to prevent the virus from invading the host cells.
T275 43308-43410 Sentence denotes In addition, glycofullerenes can be internalized into host cells losing their viral “shield” activity.
T276 43411-43546 Sentence denotes On the other hand, the well-developed surface chemistry of glycofullerenes can be used for other key receptors involved in viral entry.
T277 43547-43746 Sentence denotes For instance, in the case of the current SARS-Cov-2 pandemic, a similar click chemistry strategy can be used to anchor ligands recognized by human lung ACE2 receptors and so inhibiting viral entry.73
T278 43748-43774 Sentence denotes Other Carbon Nanomaterials
T279 43775-43891 Sentence denotes Alongside fullerenes, other carbon nanomaterials (NMs) have been scrutinized for their ability to block viral entry.
T280 43892-43978 Sentence denotes CDs and GO are the most known and studied carbon NMs with marked antiviral properties.
T281 43979-44025 Sentence denotes CDs are zero-dimensional carbon nanoparticles.
T282 44026-44128 Sentence denotes They are generally produced via hydrothermal decomposition of carbon containing “low-cost” precursors.
T283 44129-44289 Sentence denotes The use of CDs in the biomedical field has been encouraged by their easy preparation, low toxicity, fluorescence properties, and easy surface functionalization.
T284 44290-44533 Sentence denotes Pristine CDs have shown moderate viral blocking activity for HIV infection in vitro.74 This has been associated with the surface of the material rich in carboxylic and hydroxyl groups prone to form noncovalent interaction with viral membranes.
T285 44534-44697 Sentence denotes Moreover, due to the complexity of the biological systems these nonspecific interactions could not be so effective in vivo, likely reducing the antiviral efficacy.
T286 44698-44799 Sentence denotes Therapeutic targeting molecules can be grafted onto a CD surface to enhance their antiviral activity.
T287 44800-44909 Sentence denotes In this context, the design of multifunctional CD platforms can be obtained through two different strategies.
T288 44910-45049 Sentence denotes The first consists in a single-step reaction that foresees the insertion of the therapeutic molecule directly into the step of preparation.
T289 45050-45147 Sentence denotes Target molecules are decomposed with the other precursors, generating the desired functional CDs.
T290 45148-45255 Sentence denotes This protocol is fast and efficient, however the drug loading as well as its activity are hard to estimate.
T291 45256-45386 Sentence denotes Indeed, the hydrothermal treatment can alter the chemical structure of the active molecule, thus vanishing its therapeutic effect.
T292 45387-45613 Sentence denotes For these reasons, the reaction conditions must be carefully controlled.75 The second method is a two-step reaction and implies the postfunctionalization via amide formation on the surface of the CDs rich in carboxylic groups.
T293 45614-45744 Sentence denotes This strategy offers a better chemical control, but the yield and the drug loading may not be quantitative and high, respectively.
T294 45745-45820 Sentence denotes Different functionalized CDs were prepared to hamper host cell viral entry.
T295 45821-45960 Sentence denotes For instance, benzoxazine (a low water-soluble antiviral agent) was incorporated into the CD structure during their preparation (Figure 7).
T296 45961-46353 Sentence denotes The as-prepared CDs showed a broad spectrum viral blocking capacity in vitro for enveloped (e.g., Japanese encephalitis virus, Dengue virus, and Zika virus) and non-enveloped viruses (e.g., porcine parvovirus and adenovirus-associated virus).76 These positive results were explained by the efficient binding and deactivation induced by the multivalent effect of the CDs to the viral particles
T297 46354-46452 Sentence denotes Figure 7 Illustration of benzoxazine-functionalized CDs and their broad antiviral entry activity.
T298 46453-46494 Sentence denotes Reproduced with permission from ref (76).
T299 46495-46523 Sentence denotes Copyright 2019 Elsevier B.V.
T300 46524-46603 Sentence denotes Amino-functionalized CDs were also tested for the treatment of human norovirus.
T301 46604-46788 Sentence denotes In this study, CDs were functionalized with 2,2′-(ethylenedioxy)bis(ethylamine) (EDA) and 3-ethoxypropylamine (EPA) via amide bond formation.77 These NMs exerted a good viral blockage.
T302 46789-46989 Sentence denotes In particular, EPA-functionalized CDs were able to inhibit 100% of viral infection at concentration of 2 μg/mL, while in the case of CDs prepared with the other amines, 80% of inhibition was reported.
T303 46990-47086 Sentence denotes These effects have been associated with the higher positive charge of CD-EDA compared to CD-EPA.
T304 47087-47216 Sentence denotes Another surface group used for viral targeting is boronic acid (BA), which can bind glycosylated surfaces forming boronic esters.
T305 47217-47717 Sentence denotes This strategy was successfully adopted to treat HIV where the boronic groups, linked to different nanoparticles (e.g., silica nanoparticles and nanodiamonds) can target gp120 receptors on the viral envelope inhibiting the infection.78 Another recent study proposed the use of CD functionalized with phenylboronic acid for prevention of HIV infection.74 The functional materials showed good inhibition properties compared to nonfunctionalized CDs by preventing the binding to the target cell in vitro.
T306 47718-47812 Sentence denotes Overall, the use of CDs for stopping host cell viral entrance has shown good results in vitro.
T307 47813-47917 Sentence denotes However, there is a lack of proofs in vivo limiting their applications to surface disinfection or masks.
T308 47918-48064 Sentence denotes In addition, most of the in vitro studies foresee first the contact of the CDs with the viral particles and then their incubation with host cells.
T309 48065-48230 Sentence denotes Deeper investigations should be performed adding the NMs at other time points (for instance in infected cells) to understand if the antiviral activity is maintained.
T310 48231-48366 Sentence denotes In addition, CDs have been successfully used for photodynamic therapy (generating radicals upon light irradiation) in cancer treatment.
T311 48367-48551 Sentence denotes The same approach may be used to combat viral infections, where the antiviral activity induced by the surface modification can be sensibly enhanced by ROS generation under irradiation.
T312 48552-48878 Sentence denotes Graphene materials, and in particular GO and reduced GO (rGO), have been used for different biomedical applications including drug delivery, biosensing, and tissue engineering.5 GO platforms have shown also interesting antimicrobial activity.79 Regarding viral infection, GO was used to block the virus entrance in host cells.
T313 48879-49068 Sentence denotes GO and rGO can be considered as two-dimensional materials that contain hydrophilic and hydrophobic domains allowing to adsorb many biological molecules including nucleic acids and proteins.
T314 49069-49227 Sentence denotes GO showed low interaction with viruses, however its surface functionalization with target molecules can sensibly enhance its affinity for the viral particles.
T315 49228-49482 Sentence denotes Additionally, GO can be used as photothermal agent (generation of heat by NIR irradiation) or photodynamic therapy (using visible light irradiation) inactivating the capsids by local thermal shock or by radical formation during irradiation, respectively.
T316 49483-49577 Sentence denotes The use of phototherapies may significantly augment the antiviral properties of the materials.
T317 49578-49760 Sentence denotes However, we must keep in mind that these therapeutic modalities can be applied only to disinfection, since the radical/heat production may be harmful for the healthy tissues in vivo.
T318 49761-49943 Sentence denotes Photodynamic therapy has been successfully exploited using bacteriophage MS2 as a model virus.80 In this study, GO was functionalized with an aptamer recognized by the viral surface.
T319 49944-50105 Sentence denotes The results showed that this functionalization is able to enhance the binding efficiency of the MS2 capsids onto the GO surface compared to nonfunctionalized GO.
T320 50106-50272 Sentence denotes Subsequently, irradiation in the visible light was able to disinfect the solution, while nonfunctionalized GO showed much less activity due to the lack of adsorption.
T321 50273-50517 Sentence denotes Despite these interesting results, this pioneer work remains at an early research stage since the use of high light dose (300 W for 10–140 min) and the lack of material recovery and reuse make its application for surface disinfection difficult.
T322 50518-50577 Sentence denotes GO can be also used as a platform to link antiviral agents.
T323 50578-50930 Sentence denotes Encouraging results were reported using GO with hypericin for the treatment of a recently appeared duck reovirus.81 More recently, Deokar et al. reported an original rGO-based multifunctional platform for HSV-1 treatment.82 In this work, the authors functionalized the material with organic sulfate groups and iron oxide magnetic nanoparticles (FeNPs).
T324 50931-51028 Sentence denotes The rGO functionalized with the sulfate is able to mimic the host cell surface and to bind HSV-1.
T325 51029-51184 Sentence denotes Subsequently, the viral particles captured onto the rGO-FeNP surface can be concentrated via magnetic precipitation and destroyed via photothermal therapy.
T326 51185-51297 Sentence denotes This approach is highly efficient for disinfection with low energy (1.6 W/cm2 for 7 min) and cost effectiveness.
T327 51298-51533 Sentence denotes HS is a common entry receptor in various types of viruses (e.g., herpes viruses, human papillomavirus, Dengue virus).83 The use of organic sulfate-functionalized graphene sheets mimicking HS, like GO and rGO, has been already explored.
T328 51534-51914 Sentence denotes However, it is worth noting that these NMs are prone to strongly adsorb proteins in culture environments (coronation), likely inhibiting their antiviral efficacy.84 High loadings of sulfate groups were introduced onto rGO using polyglycerol sulfate.85,86 This approach has been used for inhibition of orthopoxvirus, pseudorabies virus, and African swine fever virus in vitro.85,86
T329 51915-51965 Sentence denotes Graphene has also been used as antiviral material.
T330 51966-52234 Sentence denotes Polysulfates and fatty amines were grafted onto graphene surface via triazine chemistry for the treatment of herpes simplex virus.87 This strategy promotes the synergy between the electrostatic and hydrophobic interactions, showing incredibly high inhibition efficacy.
T331 52235-52321 Sentence denotes Overall, graphene materials have shown a good capacity to block host cell viral entry.
T332 52322-52460 Sentence denotes Disinfection with graphene family materials is also promising, offering the possibility to couple high viral binding with phototreatments.
T333 52461-52634 Sentence denotes Regarding the GO and rGO activity in cellular environments, different parameters must be considered such as protein coronation, blood circulation time, and activity in vivo.
T334 52635-52742 Sentence denotes So far, the use of sulfonic groups introduced via diazonium salt decomposition has been largely privileged.
T335 52743-52934 Sentence denotes We take this opportunity to encourage future studies using other targeting groups (e.g., boronic acids) and grafting methods (e.g., epoxide ring opening or hydroxyl esterification reactions).
T336 52936-52971 Sentence denotes Mechanical Disruption of the Capsid
T337 52972-53283 Sentence denotes The most direct way to suppress viruses and stop the spreading of viral infection is to inactivate them before the attachment to the host cells, by binding to the acceptor proteins.88 One of the most conserved targets of viral attachment ligands is the heparan sulfate proteoglycan (HSPG), previously mentioned.
T338 53284-53480 Sentence denotes HSPGs are expressed on the surface of almost all eukaryotic cell types, and many viruses like HIV-1, HSV, human papilloma virus (HPV) exploit HSPGs as the target of their viral attachment ligands.
T339 53481-53650 Sentence denotes Bearing in mind this behavior, different studies have used HSPG-mimicking materials to target this type of virus–cell interaction and to achieve broad spectrum efficacy.
T340 53651-53783 Sentence denotes For example, in one key study, AuNPs were functionalized with mercaptoethanesulfonate (MES) based on its mimicry of HS (Au-MES NPs).
T341 53784-54001 Sentence denotes Au-MES NPs were shown to interfere with viral attachment, viral entry, and cell-to-cell spreading.89 The importance of the polyvalent interactions with the virus makes these NPs a good candidate for antiviral therapy.
T342 54002-54183 Sentence denotes However, Au-MES NPs presented virustatic activity, meaning that upon dilution of the NPs, the virus recovers its infectivity due to the reversibility of the cell-virion interaction.
T343 54184-54322 Sentence denotes This problem was solved by Stellacci and colleagues who developed NPs coated with mercapto-1-undecanesulfonate (MUS) ligands (Au-MUS NPs).
T344 54323-54741 Sentence denotes The long aliphatic and flexible linkers provide stronger associations with the viral particles compared to Au-MES NPs, leading to local distortions and eventually inducing a global deformation and breaking of the capsid that inactivates its contagion irreversibly (Figure 8).90 These Au-MUS NPs were tested against different HSPG-dependent viruses, showing a high viricidal activity over HSV, HPV, and RSV (Figure 9A).
T345 54742-55008 Sentence denotes Furthermore, the activity of the Au-MUS NPs was studied in vivo using mice infected with RSV, indicating that the material can prevent pulmonary dissemination of the infection and showing potential use as medically relevant virucidal drugs to fight viral infections.
T346 55009-55290 Sentence denotes More recently, the concept was further extended to cyclodextrins modified with mercapto-1-undecanesulfonate, proposing this system as a broad spectrum virucidal macromolecule.91 Besides Au-NPs, a similar mechanism of disruption was studied with other materials like graphene or GO.
T347 55291-55580 Sentence denotes In a study, in which the toxicity of graphene was evaluated theoretically, it was also shown that graphene nanosheets can interrupt the hydrophobic protein–protein interaction, which is essential to biological functions.92 This feature was attributed to the hydrophobic nature of graphene.
T348 55581-55724 Sentence denotes Thus, it seems energetically favorable for graphene to slide between the interface of two proteins in contact, due to hydrophobic interactions.
T349 55725-56269 Sentence denotes In another study inspired by this behavior, the authors performed molecular dynamics simulations of graphene nanosheets in the proximity of the surface of the Ebola viral matrix protein VP40 showing that the nanosheets can break the hydrophobic interactions in VP40, a key protein for the replication and stability of Ebola virus (Figure 8).93 These findings suggest that graphene nanosheets might have potential antiviral activity against Ebola; however, there is a lack of experimental evidence that corroborates this mechanism of disruption.
T350 56270-56726 Sentence denotes On the other hand, GO was tested experimentally against Pseudorabies virus and Porcine epidemic diarrhea virus (PEDV), showing significant decrease in the infectivity.94 It was found that the negatively charged surface of GO is important for the adsorption of the virus, whose surface is positively charged, and that GO could directly interact with the viral particles and destroy their structures due to the sharp edges of the material (Figures 8 and 9B).
T351 56727-56793 Sentence denotes Figure 8 Mechanical disruption mechanisms of different NMs. Left:
T352 56794-56886 Sentence denotes Au-MUS NPs inducing mechanical forces in the virus capsid leading to inactivation.90 Center:
T353 56887-56959 Sentence denotes Graphene NSs disrupting VP40 hydrophobic interactions in Ebola.93 Right:
T354 56960-57045 Sentence denotes Interaction between negatively charged surface of GO and positively charged capsid.94
T355 57046-57093 Sentence denotes Figure 9 Interaction of NMs with viral capsid.
T356 57094-57128 Sentence denotes A) Gold NPs acting on HSV-2 virus.
T357 57129-57205 Sentence denotes After 90 min, the percentage of destroyed virus was significantly increased.
T358 57206-57217 Sentence denotes Scale bars:
T359 57218-57225 Sentence denotes 100 nm.
T360 57226-57267 Sentence denotes Reproduced with permission from ref (90).
T361 57268-57344 Sentence denotes Copyright 2018 Springer Nature Limited. (B) GO acting on Pseudorabies virus.
T362 57345-57432 Sentence denotes After incubation with GO for 1 h, part of the virus envelope and spikes were destroyed.
T363 57433-57444 Sentence denotes Scale bars:
T364 57445-57452 Sentence denotes 200 nm.
T365 57453-57494 Sentence denotes Reproduced with permission from ref (94).
T366 57495-57537 Sentence denotes Copyright 2015, American Chemical Society.
T367 57538-57764 Sentence denotes The mechanical disruption of the capsid is a peculiar antiviral mechanism associated with some NMs. In particular, the use of specific sulfonates able to mimic heparan sulfate can be also used to target SARS-Cov-2 infection.95
T368 57766-57802 Sentence denotes Antiviral Activity Inside Host Cells
T369 57803-57944 Sentence denotes Blocking the viral entry, via liquid/surface disinfection or once in the body, is a powerful strategy to hamper early stage viral contagions.
T370 57945-58088 Sentence denotes On the other hand, when infections have already spread and reached middle and late stages, alternative pharmacological strategies are required.
T371 58089-58204 Sentence denotes The study of the viral pathogenesis and machinery inside host cells has allowed the preparation of different drugs.
T372 58205-58321 Sentence denotes Due to the present pandemic, such antiviral drugs are now of top interest in the scientific and medical communities.
T373 58322-58646 Sentence denotes So far, few antiviral drugs are clinically available, and their mechanisms of action consist on the inhibition of reverse transcriptase (HIV, hepatitis), DNA inhibition of polymerase (herpes, HIV), inhibition of protease (HIV), blockage of ion channels (influenza), and inhibition of neuramidase (HIV, influenza, hepatitis).
T374 58647-58712 Sentence denotes However, these drugs suffer from moderate to severe side effects.
T375 58713-58866 Sentence denotes Additionally, rapid mutations in the viral machinery make them resistant to the treatments, making the control and the stop of the infection challenging.
T376 58867-58929 Sentence denotes The use of HNMs in drug delivery has shown several advantages.
T377 58930-58996 Sentence denotes First, HNMs can increase drug solubility and its circulation time.
T378 58997-59162 Sentence denotes Additionally, they can be functionalized with targeting molecules able to direct the drug to the desired organs and so avoiding side effects and reducing the dosage.
T379 59163-59219 Sentence denotes More recently, new antiviral mechanisms were discovered.
T380 59220-59404 Sentence denotes In particular, it was found that different types of HNMs are able to change the ROS homeostasis in infected host cells, stopping the viral replication and preserving the cell survival.
T381 59405-59531 Sentence denotes In this section both drug delivery materials and HNMs with ROS modulation properties will be critically presented (Figure 10).
T382 59532-59617 Sentence denotes Figure 10 Illustration of NMs interacting with host cell to prevent viral spreading.
T383 59618-59670 Sentence denotes Left: NMs are used for delivery of antiviral agents.
T384 59671-59766 Sentence denotes Right: NMs can change the ROS homeostasis slowing down the infection and helping cell survival.
T385 59768-59799 Sentence denotes Nanomaterials for Drug Delivery
T386 59800-59870 Sentence denotes Different HNMs have been widely tested for drug delivery applications.
T387 59871-60006 Sentence denotes The advantages of this strategy are several including enhance drug solubility and the possibility of targeting and multivalent effects.
T388 60007-60186 Sentence denotes As a potential broad spectral antiviral agent, AgNPs can prevent the virus from adsorbing to the host cell in the early stage of infection and thus show strong antiviral activity.
T389 60187-60289 Sentence denotes After the cells are infected by the virus, there are ways to inhibit cell apoptosis (Figure 2, right).
T390 60290-60608 Sentence denotes For example, Lv et al. studied the anti-TGEV activity of AgNPs in swine testicle cells and explored the possible mechanism of AgNP inhibition of TGEV infection-induced apoptosis.18 The results showed that these AgNPs are able to decrease cell apoptosis through the activation of p38/mitochondria-caspase-3 signaling.18
T391 60609-60866 Sentence denotes Although the use of AgNPs has shown good antiviral action to further improve the therapeutic effects and reduce both side effects and drug resistance, the way of binding drugs or genes and other therapeutic agents to AgNPs has received particular attention.
T392 60867-61023 Sentence denotes It has been observed that AgNPs inhibit the activities of neuraminidase and hemagglutinin, preventing the H1N1 influenza virus from attaching to host cells.
T393 61024-61152 Sentence denotes At the same time, the potential molecular mechanisms revealed that caspase-3-mediated apoptosis was inhibited by ROS generation.
T394 61153-61211 Sentence denotes AgNPs modified with polyethylenimine (PEI) can bind siRNA.
T395 61212-61517 Sentence denotes Ag@PEI@siRNA exhibited superior abilities for enhanced cellular uptake and blocking EV71 virus infection and significantly decreased the apoptotic cell population, which prevented the spread of EV71 virus.37 In addition to drugs and siRNA, neutralizing antibodies in combination with AgNPs were developed.
T396 61518-61672 Sentence denotes The results demonstrated that there is an additive effect between the antibody and AgNPs when combined against cell-associated HIV-1 infection in vitro.96
T397 61673-61739 Sentence denotes The membranotropic properties of fullerenes were widely exploited.
T398 61740-62083 Sentence denotes For example, pristine C60, after accumulation at the cell membrane, can translocate into the cytoplasm by crossing the membrane through multiple energy-dependent pathways despite its hydrophobic character.97 Fullerenes can be made water dispersible using surfactants, sonication or first dissolving them in appropriate organic solvents (DMSO).
T399 62084-62321 Sentence denotes The use of fullerenes as inhibitors of viruses started in 1993 with a study focused on HIV infection.98 This work revealed the interaction between C60 derivatives and HIV protease through molecular modeling and experimental verification.
T400 62322-62457 Sentence denotes HIV protease (HIV-PR) is involved in the mechanism of replication in the maturation of HIV virion, cleaving newly synthesized proteins.
T401 62458-62726 Sentence denotes The active site of HIV protease has a cavity of 10 Å closed to the diameter of C60 cage.99 Molecular docking and experiments on HIV-PR catalytic activity revealed a blockage of the active site of the enzyme by van der Waals interactions leading to an antiviral effect.
T402 62727-62890 Sentence denotes The following studies were based on a structure–activity relationship between functionalized fullerenes and HIV-PR with the aim to increase the antiviral activity.
T403 62891-63306 Sentence denotes The introduction of pyrrolidinium salts onto C60 was tested against the activity of HIV-1 strain.100 In a second study, C60 bearing two ammonium groups was applied against the activity of HIV-1 and HIV-2 strains.101 The results showed the importance of having two moieties in a precise position on the fullerene cage and the influence of the charge of the different salts sensibly increasing its antiviral activity.
T404 63307-63409 Sentence denotes Further investigations using different functional groups (e.g., amino acid derivatives) were explored.
T405 63410-63727 Sentence denotes C60 functionalized with aminobutyric acid and aminocaproic acid was able to inhibit HIV viral replication at subnanomolar concentrations.63 In another work, anionic and cationic pyrrolidinium salts and amino acid functionalized fullerene derivatives were used for the inhibition of HIV reverse transcriptase (HIV-RT).
T406 63728-64093 Sentence denotes Fullerene compounds were compared to nevirapine, an available drug against HIV-RT, revealing a better inhibition compared to the pure drug.102 The antiviral property of carboxylated fullerenes was confirmed by another study.103 Results obtained in vitro on CEM cell line showed low toxicity and a submicromolar EC50 against HIV-1 and HIV-2 strain viral replication.
T407 64094-64177 Sentence denotes Several mechanisms of HIV protease inhibitors have been hypothesized and simulated.
T408 64178-64431 Sentence denotes Some studies investigated the action of fullerene derivatives on viral replication cycle and the virus maturation (Figure 11).98,104 For the latter, it was suggested an impairment due to a strong interaction between fullerene and the immature capsid.105
T409 64432-64511 Sentence denotes Figure 11 Illustration of fullerene affecting the viral replication mechanism.
T410 64512-64638 Sentence denotes Interaction between fullerene and viral protein blocking either the transcription or the translation in the viral replication.
T411 64639-64982 Sentence denotes Other RNA viruses share ways of viral replication similar to HIV.106 C60 functionalized with an amino acid derivative was investigated against Hepatitis C RNA polymerase (HCV-RP).102 This essential enzyme for viral replication was inhibited in a submicromolar range, similarly to benzo-1,2,4-thiadiazine, a potent specific inhibitor of HCV-RP.
T412 64983-65273 Sentence denotes Another publication highlighted the effect of a C70 poly(carboxylic acid) derivative on different strains of influenza virus (e.g., A, H1N1, H3N2, and B).107 The inhibition was comparable to Tamiflu, rimantadine, ribavirin, and amantadine, but the mechanism of action remains still unclear.
T413 65274-65388 Sentence denotes These data emphasize that fullerenes C60 or C70 can be potent universal antiviral drugs for RNA enveloped viruses.
T414 65389-65491 Sentence denotes However, clear elucidations of the mechanisms of action and in vivo studies are still a missing point.
T415 65492-65750 Sentence denotes Due to their high surface/weight ratio and capacity to pass through cell membranes, carbon nanotubes (CNTs) have been extensively explored for drug and gene delivery applications.108 CNTs have been also successfully used for the delivery of antiviral agents.
T416 65751-66000 Sentence denotes Compared to pristine materials, oxidized CNTs (ox-CNTs) showed an inhibitory activity for HIV viruses per se.109 This effect has been associated with the oxygenated groups that increase the hydrophilicity and the colloidal stability of the material.
T417 66001-66189 Sentence denotes The antiviral efficiency has been correlated to the ox-CNT interaction with host cells.109 However, it is not clear how and what kind of mechanism blocks the viral machinery in host cells.
T418 66190-66281 Sentence denotes Different anchoring strategies have been explored to link antiviral drugs onto CNT surface.
T419 66282-66924 Sentence denotes For instance, ox-CNTs were covalently linked to 2-amino-3-nitro-1-(3,5-dimethylbenzyl)-aniline (CHI360) and N-(2-aminophenyl-3-nitro-)-3,5-dimethylbenzenesulfonamide (CHI415), two active non-nucleoside reverse transcriptase inhibitors for HIV treatment.109 Following the covalent conjugation, only a moderate antiviral effect was observed compared to pure drugs, indicating that most probably the NM cell trafficking played a key role on the virucidal activity.109 In another study, ox-CNTs functionalized with cyclodextrin were used for the delivery of acyclovir (a prodrug inhibitor of the viral DNA polymerases) for the treatment of HSV-1.
T420 66925-67226 Sentence denotes Preliminary results showed that when acyclovir was delivered via the nanotubes, the viral antireplicative effect was higher than the free drug.110 More recently, a similar approach was applied to herpes virus using cyclodextrin and PEI-functionalized CNTs for co-delivery of cidofovir and plasmid DNA.
T421 67227-67641 Sentence denotes However, the antiviral effect of the materials was not explained, and the transfection effect was not satisfactory.111 Functionalized CNTs have been also used for delivery of ribavirin in vivo using grass carp as an animal model for the study of grass carp reovirus. ox-CNTs were first functionalized via amidation with BSA, and then ribavirin was covalently bound to the protein via esterification (Figure 12).112
T422 67642-67743 Sentence denotes Figure 12 Schematic procedure of the functionalization of single-walled CNTs (SWCNTs) and ribavirin.
T423 67744-67786 Sentence denotes Reproduced with permission from ref (112).
T424 67787-67816 Sentence denotes Copyright 2015, Elsevier B.V.
T425 67817-68038 Sentence denotes In vivo tests demonstrated that, when ribovirin was shuttled by ox-CNTs, the antiviral efficiency was significantly increased without any evident toxicity and no significant changes in ROS-generating enzymatic activities.
T426 68039-68106 Sentence denotes The use of CNTs in drug delivery is however still controversial.113
T427 68107-68196 Sentence denotes Graphene-based materials have been limitedly studied as antiviral drug delivery carriers.
T428 68197-68248 Sentence denotes Only a few examples can be found in the literature.
T429 68249-68498 Sentence denotes Graphene quantum dots (GQDs) were used for drug delivery of CHI360 and CHI415 and tested in vitro against HIV similarly to CNTs.109 Both the prepared GQD-CHI360 and GQD-CHI415 showed a high antiviral activity once into host cells, with low toxicity.
T430 68499-68612 Sentence denotes GO has been also used for the delivery of DNAzyme into hepatic cells allowing to block the hepatitis C infection.
T431 68613-68714 Sentence denotes This specific DNA single strand is able to recognize the viral mRNA and to silence its expression.114
T432 68715-68789 Sentence denotes Overall, carbon NMs proved to be interesting carriers for antiviral drugs.
T433 68790-68890 Sentence denotes However, several questions need to be answered before their safe application as antiviral materials.
T434 68891-69136 Sentence denotes Different reports have demonstrated that pristine CNTs display relevant toxicity for healthy cells, but by oxidation of the tubes, the side effects can be sensibly reduced.109 In addition, more investigations should be performed on CNT toxicity.
T435 69137-69420 Sentence denotes These nanocarriers indeed are not “innocent delivery agents”, but they play a key role in drug internalization pathway and in host cell machinery that might be averse to the expected therapeutic effects.109 So far, CNT application in biological systems has been studied for 20 years.
T436 69421-69544 Sentence denotes However, due to their possible toxicity, their real application in clinics seems to be steeper and difficult to achieve.112
T437 69546-69586 Sentence denotes Materials Tuning Reactive Oxygen Species
T438 69587-69667 Sentence denotes ROS homeostasis in infected cells has been studied for both RNA and DNA viruses.
T439 69668-70182 Sentence denotes For instance, it was shown that infection of mice with influenza A decreased the concentration of lung glutathione and the antioxidant vitamin C, providing evidence that the viral infection was associated with oxidative stress in vitro as well as in vivo.115 Similarly, in HIV infection, induced oxidative stress in host T cells and high concentrations of antioxidants are able to slow down the cell-to-cell viral spreading.115 The increase of ROS concentration is a common process in most of the viral infections.
T440 70183-70259 Sentence denotes However, the mechanism of radical generation is different from case to case.
T441 70260-70373 Sentence denotes Several proofs suggest that modulating ROS homeostasis in infected cells can slow down or block the infection.116
T442 70374-70442 Sentence denotes HNMs have been shown to be powerful allies against viral infections.
T443 70443-70564 Sentence denotes In particular, metal or metal oxide NMs, once internalized, can regulate the radical production into infected host cells.
T444 70565-70713 Sentence denotes In this scenario, the NMs can work following two different mechanisms: (1) enhancing radical activity or (2) quenching ROS inside cell compartments.
T445 70714-70865 Sentence denotes In the first case, metal oxide NPs are able to convert superoxide ions into more reactive hydroxyl radical species via Fenton or Fenton-like reactions.
T446 70866-71005 Sentence denotes The excess of superoxide ions is able to oxidize the viral proteins and the genetic material and therefore efficiently block the infection.
T447 71006-71184 Sentence denotes This approach has been reported using ZnO NPs.117,118 In these studies, ZnO NPs have been successfully applied for the treatment of H1N1 influenza virus and Herpes simplex virus.
T448 71185-71328 Sentence denotes The preliminary results showed that PEGylated ZnO particles were able to efficiently reduce the viral infection with IC50 similar to acyclovir.
T449 71329-71520 Sentence denotes More importantly, toxicity of ZnO was modulated by functionalization with PEG, which allowed a higher colloidal stability and a more controlled release of Zn2+ ions to catalyze ROS formation.
T450 71521-71726 Sentence denotes Indeed, ROS (e.g., superoxide and hydroxyl radicals) produced by the NPs should be highly reactive and should not only damage the exogenous biological molecules but also attack different cell compartments.
T451 71727-71800 Sentence denotes Overproduction of ROS may reduce virus spread but also induce cell death.
T452 71801-71980 Sentence denotes Interestingly, this approach is applicable only at the early infection stage (after 1 h incubation of the host cells with a virus), but it loses its activity at later time points.
T453 71981-72373 Sentence denotes These experimental evidences suggest that materials capable of triggering the formation of ROS are essential in the first phase of the viral replication, most probably inducing the arrest of the viral DNA polymerases, which is active in the first 1–3 h of viral contamination.117,118 This specific mechanism of action restricts ZnO NPs to an application only at the early stage of infections.
T454 72374-72515 Sentence denotes However, the same approach with other metals able to induce Fenton or Fenton-like reactions (e.g., Fe, Cu, and Mn) has not been reported yet.
T455 72516-72645 Sentence denotes The choice of proper capping agents may allow to control the metal ion release and thus tune the ROS-mediated antiviral activity.
T456 72646-72752 Sentence denotes We would like to take an advantage here to suggest the growth of the antiviral research in this direction.
T457 72753-72840 Sentence denotes Another successful approach relies on the reduction of ROS concentration in host cells.
T458 72841-72990 Sentence denotes ROS scavenging is able to alleviate the toxicity of the infection enhancing cell viability, giving time to start its endogenous antiviral mechanisms.
T459 72991-73064 Sentence denotes So, this approach may both block infection and ensure host cell survival.
T460 73065-73162 Sentence denotes In this context, selenium NPs (SeNPs) have been extensively studied for their antiviral activity.
T461 73163-73454 Sentence denotes The mechanism of action of these NPs relies on the quenching of the radicals into host cells due to the infection, stopping the mitochondria depolarization and the consequent apoptotic cascade.119 Additionally, SeNPs can also adsorb onto the viral capsid sensibly reducing their infectivity.
T462 73455-73562 Sentence denotes SeNPs can be prepared via classical mixing of selenium salt precursors in the presence of a reducing agent.
T463 73563-73996 Sentence denotes More recently, SeNPs have been instead biosynthesized from Actinobacteria showing good stability and capacity to inhibit Dengue virus in vitro.120 Moreover, SeNPs were used to carry different antiviral drugs including zanamivir,121 oseltamivir,122 amantadine,123 and ribavirin.119 Their functionalization with the desired drug can be easily achieved adding the molecule during their synthesis through the Se ion controlled reduction.
T464 73997-74057 Sentence denotes These NMs have been applied for the treatment of H1N1 virus.
T465 74058-74316 Sentence denotes Notably, SeNPs with ribavirin (administered via intranasal absorption every 24 h for 3 days) showed that infected mice had much less alveolar collapse and perivascular and peribronchiolar edema, compared to the group challenged with the virus (Figure 13).119
T466 74317-74617 Sentence denotes Figure 13 In vivo antiviral efficiency of SeNPs functionalized with ribavirin (Se@RBV). (a) Mice infected by H1N1 virus were treated with physiological saline (Mock), RBV, SeNPs, or Se@RBV. (b) H&E and tunnel staining showing that Se@RBV-treated mice displayed reduced lung damages compared to Mock.
T467 74618-74660 Sentence denotes Reproduced with permission from ref (119).
T468 74661-74691 Sentence denotes Copyright 2018 Dove Press Ltd.
T469 74692-74837 Sentence denotes Due to their efficacy and low toxicity, SeNPs can be considered a useful material for the treatment of other viral diseases including SARS-Cov-2.
T470 74838-75158 Sentence denotes As a matter of fact, oxidative stress as well as chronic inflammation may contribute to the aggravation of the Covid-19 symptoms and to the general spread of the infection.124 The use of SeNPs could eventually alleviate the toxicity of infected patients, giving time for the immune system to react against the contagion.
T471 75159-75351 Sentence denotes However, the lack of preclinical studies on SeNPs, together the scarce knowledge of their biosafety and long-term toxicity, still remain the main challenges to tackle for clinical translation.
T472 75353-75387 Sentence denotes Interaction with the Immune System
T473 75388-75524 Sentence denotes The vast majority of the studies show that human survival to viral attack is based on the stimulation and response of our immune system.
T474 75525-75674 Sentence denotes When a virus enters and starts infecting tissues, the body reacts and triggers a strong immune response to overcome the pathogen invasion and spread.
T475 75675-75734 Sentence denotes Normally, two different immunological reactions take place.
T476 75735-76422 Sentence denotes The oxidative stress induced by infection causes the activation of the inflammasome through upregulation of pro-inflammatory cytokines such as IL-1β, pro-IL-18, and NLRP3.122 Excessive upregulation of this mechanism leads to cell damage and eventually to pyroptosis activated by caspases.122 It was also shown that generation of radicals is able to depolarize mitochondria, hence affecting host cell respiration and inducing ROS-mediated apoptosis at the late stage of infection.123 Besides, activation of pro-inflammatory cytokines can alert the immune system blocking the infection (the innate immune response).122 The second immune response is specific (the adaptive immune response).
T477 76423-76558 Sentence denotes Immune cells are trained to attack the virus (cellular response), while specific antibodies are produced by B cells (humoral response).
T478 76559-76692 Sentence denotes In the last years, HNMs were proved to tune the immune responses, demonstrating to be a possible alternative against viral infection.
T479 76693-76837 Sentence denotes In this section the most relevant strategies for the activation of innate and adaptive immune responses using NMs will be described (Figure 14).
T480 76838-76904 Sentence denotes Figure 14 Illustration of HNM interaction with the immune system.
T481 76905-77007 Sentence denotes Left: HNMs can enhance the production of interferon (IFN) alerting the immune system of the infection.
T482 77008-77014 Sentence denotes Right:
T483 77015-77212 Sentence denotes Virus-mimicking particles composed of viral proteins and HNMs can induce a strong immunological response activating dendritic cells, T cells, and stimulating B cells to produce specific antibodies.
T484 77214-77236 Sentence denotes Innate Immune Response
T485 77237-77340 Sentence denotes Innate immune response is the first response that takes place in the presence of any type of infection.
T486 77341-77737 Sentence denotes During this early stage, interferon stimulating genes (ISGs) are upregulated in the infected cells.125 This self-defense mechanism slows down the viral replication and alerts sentinel immune cells that start producing proinflammatory cytokines and trigger inflammation.125 However, many viruses are able to escape this complex mechanism, retarding the immune response and spreading the infection.
T487 77738-77816 Sentence denotes The interaction of HNMs with the immune system has been more and more studied.
T488 77817-77981 Sentence denotes In the case of antiviral HNMs, many examples can be found in the literature where the NMs not only slow down the infection but also tune the innate immune response.
T489 77982-78039 Sentence denotes Certain HMNs can display an intrinsic immune stimulation.
T490 78040-78322 Sentence denotes We have already mentioned above that in the early stage of infection, AgNPs mainly prevent the virus from entering the host cell through the interaction with the external capsid, but in vitro cellular experiments lack to understand the complex interaction with primary immune cells.
T491 78323-78527 Sentence denotes Recent studies have shown that AgNPs can potentially induce the expression of genes involved in innate and adaptive immunity-associated pathways, which are known to play crucial role in immune regulation.
T492 78528-79166 Sentence denotes For example, Toll-like receptor 7 can be upregulated by AgNPs after 24 h, by recognizing the single-stranded RNA of the viruses and regulating the antiviral immune response.126 Another study showed that in RSV-infected mice treated with AgNPs, the particles reduced the production of pro-inflammatory TNF-α and IL-6 cytokines, but potentiated the anti-RSV activity of neutrophils in an experimental mouse model.127 However, activation of AgNPs in the reduction of RSV has been noted only when the NM was intranasally inoculated together with the virus, and no results have been reported on the use of AgNPs administrated on infected mice.
T493 79167-79353 Sentence denotes In the case of influenza virus infection of lung epithelial cells, it was found that AgNPs targeted infected lung epithelial cells and reduced viral replication, by preventing autophagy.
T494 79354-79469 Sentence denotes However, the blockage of the autophagic flux by AgNPs does not inhibit viral replication in already infected cells.
T495 79470-79853 Sentence denotes Therefore, AgNPs are more suitable as viral preventive agents due to their pro-inflammatory response rather than drugs.128 More recently, AgNPs were combined with graphene materials and exploited as antiviral material for the treatment of Porcine reproductive and respiratory syndrome virus (PRRSV).129 GO-AgNPs were able to clump the virus diminishing its fusion with cell membrane.
T496 79854-80024 Sentence denotes Additionally, once GO-AgNPs were internalized in host cells, they stimulated the ISGs that blocked viral budding and its diffusion to other cells in vitro (Figure 15).129
T497 80025-80115 Sentence denotes Figure 15 Scheme of the mechanism of action of GO-AgNPs on activation of innate immunity.
T498 80116-80158 Sentence denotes Reproduced with permission from ref (129).
T499 80159-80201 Sentence denotes Copyright 2018 American Chemistry Society.
T500 80202-80845 Sentence denotes Similarly, CDs used for the treatment of RSV and PRRSV were able to activate the innate immune response via an upregulation of ISGs in vitro.130 Gold nanorods were applied to boost the innate immune response against RSV in vivo.131 Interestingly, it was shown that these nanorods (when intranasally administered with RSV) were not only able to activate the ISGs but also to tune the production of pro- and anti-inflammatory cytokines, resulting in the blocking of the infection with a reduced pulmonary inflammation.131 As drug carriers, HNMs can also affect the internalization pathways, modulate drug efficacy, and the immune cell responses.
T501 80846-81163 Sentence denotes For instance, it was found that the isoprinosine immunomodulatory antiviral drug displays a much higher antiviral efficacy in vivo when delivered with CNTs than as a pure drug (in zebrafish larvae food administration), probably due to a better cellular uptake and the anti-inflammatory properties of the nanotubes.132
T502 81164-81612 Sentence denotes Fullerenes also exhibit immunomodulation properties through the release of cytokines by bovine alveolar macrophages.133 A study explored the influence of functionalization of C60 with molecules presenting different surface charges like hydroxyl groups and amino acids.134 The study concluded that negative charges upregulated TNF-α up-secretion in RAW 264.7 macrophages, but highly positively or negatively charged surfaces increased cell toxicity.
T503 81613-81715 Sentence denotes The upregulation of the cytokine TNF-α is a proof that fullerene can promote cellular immune response.
T504 81716-81865 Sentence denotes Despite these preliminary results, the actual mechanisms of interaction between HNMs and the immune system are still at early stage of understanding.
T505 81866-81956 Sentence denotes We must consider that the immune response needs to be proportional to the infection grade.
T506 81957-82204 Sentence denotes If on one side nanosized immuno-boosters can alert more efficiently the sentinel cells, the use of HNMs that trigger an exaggerated immune response can promote excessive inflammation, damaging healthy cells and promoting uncontrolled side effects.
T507 82205-82424 Sentence denotes In the particular context of SARS-Cov-2, the use of AgNPs, fullerenes, or other pro-inflammatory HNMs at the middle and late infection stage may cause an aggravation of the symptoms due to already diffused inflammation.
T508 82425-82867 Sentence denotes In particular, most of the studies showed the ability to reduce infection when HNMs were first incubated with the pathogenic virus, thus limiting their potential use in the early stage infection.124 The formulation of HNMs able to both alert the immune system (e.g., upregulating cytokine) and control lung inflammation (e.g., ROS scavenger) even after the early stage infection may be a possible strategy for treatments against SARS viruses.
T509 82869-82893 Sentence denotes Adaptive Immune Response
T510 82894-82992 Sentence denotes Adaptive immune response is the specific response that the immune system exerts against pathogens.
T511 82993-83456 Sentence denotes This mechanism is particularly active toward viral infections where the immune system produces specialized lymphocytes (to fight the virus), called memory B cells (to be effective in case of new infections) and antibodies (corresponding to the humoral response).135 The stimulation of adaptive responses in case of specific infections can be induced artificially through the introduction of attenuated pathogens, stimulating the production of specific antibodies.
T512 83457-83865 Sentence denotes This is the principle of vaccination, which is the most common procedure for immunization of large areas of population against many kinds of lethal viruses.135 Besides, the use of viral proteins as antigens in the vaccine formulation leads to neutralizing antibodies, but, due to the low immunogenicity of isolated proteins, does not always stimulate sufficiently the immune system to reach total protection.
T513 83866-83969 Sentence denotes More recently, nanotechnology has been applied to develop more efficient vaccines (e.g., nanovaccines).
T514 83970-84300 Sentence denotes The use of nanostructures with a size similar to virus (virus-like nanoparticles) sensibly enhances the response helping to reach immunity.135 HNMs can adsorb viral particles and present them to the immune system.136,137 This method of vaccination has been successfully applied in vivo for the challenge of herpes simplex 2 virus.
T515 84301-84402 Sentence denotes HSV-2 starts its spreading in vaginal tissues and then diffuses to the neurons causing death in mice.
T516 84403-84599 Sentence denotes ZnO NPs (teardrop morphology), after vaginal inoculation with HSV-2, are able not only to prevent viral cell adhesion but also to expose viral antigens to T cells and DCs, leading to immunization.
T517 84600-84684 Sentence denotes The preclinical trials against HSV-2 showed a survival to infection higher than 90%.
T518 84685-84847 Sentence denotes This approach highlights the possibility to couple cell mimicking NMs to other co-adjuvants for the formulation of large spectrum nanovaccines (Figure 16).136,137
T519 84848-85203 Sentence denotes Figure 16 (A) Scanning electron microscopy images of ZnO tetrapod nanoparticles (ZOTEN) synthesized by flame transport synthesis. (B) Mice were challenged intravaginally with HSV-2 333 with or without ZOTEN. (C) To monitor progression of infection, mice were observed daily for the development of lesions around the vaginal opening, and base of the tail.
T520 85204-85271 Sentence denotes Representative images from three independent experiments are shown.
T521 85272-85314 Sentence denotes Reproduced with permission from ref (137).
T522 85315-85377 Sentence denotes Copyright 2016 the American Association of Immunologists, Inc.
T523 85378-85470 Sentence denotes HNMs have been also applied to the delivery of antigens, exposing them to the immune system.
T524 85471-86100 Sentence denotes Fullerenes were found as suitable carriers for the delivery of drugs or nucleic acids.138 Functionalized fullerene can also self-assemble into virus-sized NPs.139 Investigated as vaccines in cancer immune therapy,140 polyhydroxy fullerenes (called fullerenols) display interesting properties for antiviral therapy, based on their capacity to self-assemble into virus-like particles (VLPs) and so to enhance the immunogenicity of the antigens.141 The great advantage of this strategy relies on the easy encapsulation process during the self-assembly making fullerenols versatile for the formulation of different kinds of vaccines.
T525 86101-86524 Sentence denotes These VLPs were investigated against HIV-1141 and hepatitis C viruses.142 Compared to conventional protein- or peptide-based vaccines intended to induce antigen-specific adaptive immune responses, DNA vaccines are more stable, cost-effective, easy to manufacture, and safe in handling.143 However, DNA vaccines have the disadvantage of being poorly immunogenic.144 Fullerenol VLPs allow to avoid the use of other adjuvants.
T526 86525-86662 Sentence denotes In the case of a vaccine against HIV-1, fullerenol VLPs penetrated easily into the cells resulting in an enhancement of DNA transfection.
T527 86663-86893 Sentence denotes This was proved in a study using fullerenol encapsulating DNA encoding the HIV-1 envelope protein gp145 (Figure 17).141In vitro assays were performed in human embryonic kidney cells line (HEK293) showing good transfection ability.
T528 86894-87087 Sentence denotes Following various immunization routes (e.g., activation of Toll-like receptor signaling or effector memory T cell immune response), fullerenol VLPs can induce an innate and a cellular immunity.
T529 87088-87260 Sentence denotes A similar study was performed for hepatitis C using the HCV recombinant protein as antigen,142 confirming the potential efficacy of using fullerenols as antiviral vaccines.
T530 87261-87332 Sentence denotes Nevertheless, these results require further mechanistic investigations.
T531 87333-87630 Sentence denotes Indeed, in vitro studies also evidenced a suppressive effect of acquired immune response of C60 pyrrolidine tris-acid and fullerenol C60(OH)36.145 The fullerenol had a dose-dependent effect on T cell receptor-mediated activation and antibody production by B cells under anti-CD40/IL-4 stimulation.
T532 87631-87681 Sentence denotes However, the molecular mechanism is still unknown.
T533 87682-88311 Sentence denotes Figure 17 Use of fullerenol as co-adjuvant for vaccination. (a) The structure of fullerenol, red balls represent O and white for H on the fullerene surface, and green balls represent C atoms. (b) The schematic diagram of HIV Env plasmid DNA encapsulated during the self-assembly of fullerenol. (c) TEM image of Env entrapped by fullerenol. (d) Compared to naked Env immunization group, IFN-γ production (immunospot) was significantly enhanced when mice were immunized with the formulation via various immunization routes, including intradermal (i.d.), intramuscular (i.m.), subcutaneous (s.c.), and intranasal (i.n.) injections.
T534 88312-88388 Sentence denotes Fullerenol could decrease the antigen dosage (e) and immunization times (f).
T535 88389-88431 Sentence denotes Reproduced with permission from ref (141).
T536 88432-88470 Sentence denotes Copyright 2013 John Wiley & Sons, Inc.
T537 88471-88909 Sentence denotes Other HNMs including AuNPs (two subcutaneous injections in guinea pigs) and nanodiamonds (three subcutaneous injections in Balb/C mice) were explored as carriers of viral proteins for immunization of swine transmissible gastroenteritis virus and H7N9 influenza, respectively, with good preliminary results.146,147 In these cases, the vaccine formulation relies on the adsorption of the viral antigen onto the surface of the nanoparticles.
T538 88910-88971 Sentence denotes However, an effective vaccination depends on several factors.
T539 88972-89044 Sentence denotes First of all, the size of the NPs plays a key role on the immune system.
T540 89045-89278 Sentence denotes For instance, size-dependent vaccination efficacy has been reported in mice immunization against the foot-and-mouth disease virus (intraperitoneal and subcutaneous injection, every 7 days for 7 weeks) using AuNPs as antigen carriers.
T541 89279-89500 Sentence denotes In this study, the most effective activity to stimulate the immune system was exerted by particles with a diameter in the range of 8 nm.148 Both smaller or bigger particles evidenced a drop-off of the immunization effect.
T542 89501-89670 Sentence denotes This aspect cannot be ascribed to the antigen concentration, but must be associated only to the nanoparticle size; however, the mechanism of interaction remains unknown.
T543 89671-89763 Sentence denotes The selected antigen plays also a crucial role in the preparation of wide spectrum vaccines.
T544 89764-89902 Sentence denotes For instance, in the case of influenza, two major membrane glycoproteins, hemagglutinin and neuraminidase, are generally used as antigens.
T545 89903-90118 Sentence denotes However, the antibodies produced by this vaccination strategy are selective to the dominant epitope which has a low effectiveness or is totally ineffective against other epitopes or other kinds of influenza viruses.
T546 90119-90325 Sentence denotes M2 (a viral protein responsible for the budding and scission of the influenza virus) is commonly expressed in different types of influenza viruses with a high rate of conservation but with low antigenicity.
T547 90326-90456 Sentence denotes It has been shown that AuNPs functionalized with M2e protein have a high immunization capacity in comparison to the antigen alone.
T548 90457-90791 Sentence denotes Mice immunized with AuNPs (two intranasal injections), and then challenged, showed a survival rate higher than 90% to California-H1N1pdm, Victoria-H3N2, and Vietnam-H5N1 infections.149 This strategy shows that HNMs can be used to boost the immune response of low immunogenic molecules, providing a wide spectrum vaccination potential.
T549 90792-91024 Sentence denotes Unfortunately, it has not been determined if the budding process in SARS-Cov-2 is mediated by viral proteins or via the host cell’s endosomal sorting complex, thus more research on the SARS-Cov-2 viral machinery is highly desirable.
T550 91025-91239 Sentence denotes All these approaches are based on the capacity of the nanoparticles to adsorb the antigens and expose them to the immune system in the appropriate conformation to produce the neutralizing and protective antibodies.
T551 91240-91298 Sentence denotes However, the adsorption is not an easy process to control.
T552 91299-91549 Sentence denotes For instance, AuNPs have been ineffective in the immunization against SARS-Cov, when S viral proteins were used as antigens.150 In particular, the immunization with the protein alone was more efficient than when it was adsorbed onto the AuNP surface.
T553 91550-91704 Sentence denotes This failure was associated with a conformational change or denaturation of the antigen, which did not lead to the production of the specific antibody.150
T554 91705-92428 Sentence denotes Covalent chemistry strategies offer a higher control on the antigen quantification with higher reproducibility and possibility to bind different groups onto the surface of HNMs. For example, calcium phosphate nanoparticles (CaPNPs) were successfully covalently functionalized with Hen Egg lysozyme as model antigen showing an immunization 100 times higher in vivo compared to antigens alone using (one subdermal injection in mice).151 A similar approach was used with iron oxide NPs using mannose (to target DCs) and hepatitis B antigen showing good immunological activity in vitro (two subdermal injections in mice at 14 days distance).152 More recently, other types of vaccination strategies have been applied using HNMs.
T555 92429-92508 Sentence denotes A smart example has been reported using multifunctional CaPNPs on herpes virus.
T556 92509-92659 Sentence denotes In this study, CaPNPs have been covalently functionalized with alum/MPL as the adjuvant and two peptides as antigens selected via reverse vaccination.
T557 92660-92957 Sentence denotes The NM stimulated the immune system generating highly efficient antibodies able to block cell-to-cell infection of herpes virus in vivo (three intramuscular injections in mice every 14 days), increasing the survival rate of immunized mice to 100% against the controls (20% survival, Figure 18).153
T558 92958-93003 Sentence denotes Figure 18 Scheme of CaPNPs used for vaccine.
T559 93004-93009 Sentence denotes Left:
T560 93010-93090 Sentence denotes CaPNPs functionalized with CpGm adjuvant and two different peptides as antigens.
T561 93091-93101 Sentence denotes Top right:
T562 93102-93164 Sentence denotes CaPNPs were able to reduce cell-to-cell virus spread in vitro.
T563 93165-93178 Sentence denotes Bottom right:
T564 93179-93237 Sentence denotes CaP nanovaccines were able to immunize mice against HSV-1.
T565 93238-93280 Sentence denotes Reproduced with permission from ref (153).
T566 93281-93309 Sentence denotes Copyright 2019 Elsevier B.V.
T567 93311-93335 Sentence denotes Summary and Perspectives
T568 93336-93437 Sentence denotes The recent history has shown the spread of different viral pandemics such as H1N1 flu, HIV, and SARS.
T569 93438-93600 Sentence denotes Nowadays, the SARS-Cov-2 pandemic global lockdown has profoundly changed the daily life of most humans, causing uncertainty in short and middle time perspectives.
T570 93601-93766 Sentence denotes In this context, the scientific community has responded to protect the population by studying new vaccines and disinfection methods to be applied in the near future.
T571 93767-93931 Sentence denotes Despite this tough work, a SARS-Cov-2 vaccination will hopefully be available in 1–2 years, making this epidemic transient period gloomy with increased instability.
T572 93932-94056 Sentence denotes The study of more effective vaccines and the production of a wide range antiviral agents is nowadays an extremely hot topic.
T573 94057-94163 Sentence denotes HNMs comprise a family of materials that share a nanostructured hard core and a tunable surface chemistry.
T574 94164-94256 Sentence denotes In this contribution, we have methodically reviewed different HNMs for antiviral properties.
T575 94257-94424 Sentence denotes HNMs can have antiviral properties per se, blocking the viral replication and diffusion, or their antiviral properties can be tailored, playing with surface chemistry.
T576 94425-94503 Sentence denotes HNMs can be used to block viral entry and arrest infection at the early stage.
T577 94504-94755 Sentence denotes The mechanisms rely on different actions including breaking of capsid disulfide bonds (e.g., noble metal nanoparticles), capsid oxidation (e.g., CuONPs), mimicking of cell surface (e.g., carbon NMs), or mechanical disruption (e.g., AuNPs or graphene).
T578 94756-94879 Sentence denotes Surface functionalization additionally confers a higher specificity and pharmacological activity toward the targeted virus.
T579 94880-95185 Sentence denotes In particular, the high local concentration of ligands on functionalized HNM surface imparts a high multivalent effect, enhancing the viral trapping efficiency of NMs. Interestingly, HNMs that show an intrinsic antiviral activity can further enhance their antiviral efficacy via surface functionalization.
T580 95186-95364 Sentence denotes Some antiviral HNMs are good photosensitizers (e.g., CuONPs) or exert photothermal activity (e.g., carbon NMs), thus their antiviral activity can be trigged by light stimulation.
T581 95365-95501 Sentence denotes More importantly, most of the settled strategies target common viral entry mechanisms and can be adopted to fight a wide viral spectrum.
T582 95502-95587 Sentence denotes HNMs have been also applied as antiviral agents by their interaction with host cells.
T583 95588-95720 Sentence denotes HNMs are able to block viral replication machinery in host cells (e.g., CNTs and fullerenes), inhibiting endogenous enzyme activity.
T584 95721-95880 Sentence denotes Additionally, HNMs can be explored for the delivery of antiviral molecules, showing a better antiviral activity and reducing side effects in vitro and in vivo.
T585 95881-96014 Sentence denotes Some HNMs can also regulate the ROS homeostasis of host cells, reduce apoptosis, and enhance host cell survival during the infection.
T586 96015-96070 Sentence denotes Finally, we have reviewed the role of HNMs on immunity.
T587 96071-96192 Sentence denotes In particular, HNMs can stimulate the innate immune response, mainly inducing overexpression of interferon and cytokines.
T588 96193-96284 Sentence denotes This effect can alert sentinel cells and generally warn the immune system of the infection.
T589 96285-96382 Sentence denotes HNMs can be also used for the activation of the adaptive immune response, foreseeing vaccination.
T590 96383-96520 Sentence denotes Due to the similar size of a virus, functionalized HNMs with antiviral molecules (virus-like particles) can enhance their immunogenicity.
T591 96521-96605 Sentence denotes Certainly a huge effort should be done for translation of the research into clinics.
T592 96606-96686 Sentence denotes Indeed, HNM applications as antivirals are still in the early phase of research.
T593 96687-96753 Sentence denotes Several challenges still need to be tackled before their safe use.
T594 96754-96835 Sentence denotes At the current stage, some HNMs have been approved only for surface disinfection.
T595 96836-97004 Sentence denotes For instance, CuNPs have been used in filters for the preparation of highly efficient broad spectrum antiviral masks.50 Some HNMs have been already clinically approved.
T596 97005-97340 Sentence denotes For example, FeNPs were approved for imaging and as a drug to treat iron deficiency anemia in adult patients with chronic kidney disease, while AuNPs are in clinical trials for the treatment of prostate cancer (photothermal therapy).154,155 However, at the moment no clinical trials are running for the use of HNMs as antiviral agents.
T597 97341-97432 Sentence denotes In fact, there are still several concerns on the applications of HNMs in drug formulations.
T598 97433-97571 Sentence denotes Compared to molecules, where mainly concentration and exposure routes are concerned, solving HNM toxicity issues is much more complicated.
T599 97572-97700 Sentence denotes Composition, size, shape, and surface functionalization must be considered to respond to the requirement for safety regulations.
T600 97701-97784 Sentence denotes Additionally, interaction on HNMs with the immune system must be better elucidated.
T601 97785-98260 Sentence denotes In particular, the activation of the immune system and complement activation-related pseudoallergy must be taken into account.156 For instance, ferumoxytol (a FeNP-based drug) has been reported to generate severe anaphylactic reactions in humans, 18 of which were fatal.156 This is due to the possible interaction of HNMs with mast cells, provoking their degranulation/activation and release of histamine even at the first exposure (pseudoallergic-mediated hypersensitivity).
T602 98261-98598 Sentence denotes Besides, the mechanism of activation of these cells is still unknown, although it was found that it depends on the HNM composition, size, and surface chemistry and on the corona formation.156 On the other hand, it has been demonstrated that HNMs can travel to the draining lymph nodes, targeting resident dendritic cells and macrophages.
T603 98599-98993 Sentence denotes Therefore, they are able to interact with antigen presenting cells to stimulate innate and adaptive immune responses.156 We believe that a joint venture of different chemists, materials scientists, virologists, toxicologists, and medical doctors can push forward the preparation and safe application of HNMs in this field, hoping to prevent and eventually block the rise of new viral pandemics.
T604 98995-99047 Sentence denotes The authors declare no competing financial interest.
T605 99049-99064 Sentence denotes Acknowledgments
T606 99065-99164 Sentence denotes The authors gratefully acknowledge the financial support from the EU Graphene Flagship project (no.
T607 99165-99173 Sentence denotes 881603).
T608 99174-99326 Sentence denotes This work was partly supported the Agence Nationale de la Recherche (ANR) through the LabEx project Chemistry of Complex Systems (ANR-10-LABX-0026_CSC).
T609 99327-99478 Sentence denotes We wish to acknowledge the Centre National de la Recherche Scientifique (CNRS) and the International Center for Frontier Research in Chemistry (icFRC).
T610 99479-99595 Sentence denotes S.P. is indebted to the Chinese Scholarship Council for supporting her Ph.D. internship as a visiting Ph.D. student.
T611 99596-99701 Sentence denotes A.F.A. wish to thanks the EUR CSC Graduate School (Strasbourg, France) for supporting his Master studies.
T612 99702-99712 Sentence denotes Vocabulary
T613 99713-99816 Sentence denotes Hard nanomaterial nonpolymeric organic or inorganic materials with sizes comprised between 1 and 100 nm
T614 99817-99938 Sentence denotes antiviral medical term used for any agent or drug altering virus integrity or process involved in viral infection disease
T615 99939-100060 Sentence denotes viral infection process by which viruses invade the body through multiple pathways and multiply in susceptible host cells
T616 100061-100353 Sentence denotes viral pathogenesis approach in biomedical research to understand the process by which a viral infection leads to disease, including mechanism of infection into the host (e.g., viral entry, viral replication) and factors that affect this mechanism (e.g., virus susceptibility to host defenses)
T617 100354-100445 Sentence denotes membranotropism the ability of an organism or an agent to interact with biological barriers
T618 100446-100621 Sentence denotes immunogenicity capacity of an exogenous substance or material to trigger an immune response in humans and other animals or to induce a humoral and/or cellular immune responses
T619 100622-100739 Sentence denotes multifunctional platform material modified with different functionalities to achieve a variety of combined treatments