PMC:7299399 / 55897-65207 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7299399","sourcedb":"PMC","sourceid":"7299399","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7299399","text":"SARS-CoV-2 Inactivation by Nano-Based Tools\nSilver, copper, and zinc show intrinsic antimicrobial properties and are already used in medical equipment and in healthcare settings. For instance, Ag is used in wound dressing and in urinary and intravascular catheters. It is advantageous to use NPs composed of these metals rather than bulk materials or the metal ions themselves because NPs release the toxic metal ions slowly and progressively right where the antimicrobial action is needed and because NPs can accumulate within cells without being expelled by specialized efflux pumps. The antimicrobial property of Ag has been used since ancient times for medical applications154 and more recently in commercial products such as silver zeolites in paints155 and in food trays156 as biocide. The antiviral efficiency of Ag NPs has been demonstrated in a variety of viruses, including HIV-1,157 monkeypox virus,158 bacteriophages UZ1 and MS2,159,160 murine norovirus MNV1,159,160 HSV,161 HBV,162 and, recently, in porcine epidemic diarrhea virus (PEDV).163Antiviral properties of Ag NPs arise from three different mechanisms. First, Ag(0) NPs dissolve and release some toxic Ag(I) forms (including Ag+ ions), which could be responsible for their antiviral activity. As a soft metal, Ag shows strong affinity toward sulfur, and therefore, it interacts strongly with thiols from small molecules such as cysteine or glutathione or with sulfhydryl groups in the active sites of many enzymes. Ag(I) may interact with surface proteins of viruses or accumulate in host cells and further interact with thiol-containing enzymes that are involved in virus replication, thus hampering their functions. This hypothesis was proposed by Zodrow et al. to explain the antiviral property of Ag NPs for bacteriophage MS2 and by De Gusseme et al. in response to MNV-1 exposed to Ag NPs.159,164 Moreover, Ag2S nanoclusters (NCs) with diameters of 2.5 and 4 nm showed effective inhibition of PEDV replication in Vero cells via inhibition of the synthesis of viral negative-strand RNA and of virus budding from the cells, but not by preventing their anchorage on cell membranes or their intracellular penetration. Exposing cells to Ag+ ions at the same concentration did not inhibit virus replication, which led the authors to conclude that the antiviral property of Ag NCs was independent of the release of Ag(I).163 However, the mechanisms by which Ag+ ions and Ag NCs enter into cells are different and, consequently, their local distribution and handling within cells would also be different. This difference could lead to different modes of toxic action for Ag ions and Ag NCs toward the viruses that have infected cells. For instance, Ag NCs may aggregate in intracellular areas where vital steps of the viral cycle are performed, such as protein or genome production or assembly of nucleocapsids before their release into the extracellular space, whereas Ag(I) could aggregate in other areas of the cells or be rapidly eliminated. Second, the antiviral efficiency of Ag NPs would derive from physical interaction of Ag NPs with the surface of viruses, which would impede their docking on host cells and limit their infectivity. This mechanism was demonstrated by Elechiguerra et al. for HIV-1 exposed to 1–10 nm Ag NPs157 and by Orlowski et al. for HSV-2 exposed to 13, 33, and 46 nm Ag NPs coated with tannic acid.161 Elechiguerra et al. found that the optimal size of Ag NPs was around 10 nm, with larger or smaller NP sizes showing weaker physical interaction with the virus. In contrast, Orlowski et al. found that the larger the NP, the more effective its blocking was of virus attachment to host cell. The same mechanism, combined with the release of Ag(I), was also proposed by De Gusseme et al. to explain the reduced infectivity of MNV-1 virus when exposed to 11.2 nm biogenic Ag NPs.159 Finally, this docking of Ag NPs on the surface of viruses could be associated with the local release of ROS from the Ag NP surface, which would damage the envelope and/or membrane of the virus. Ag NPs are already used in wound dressings, catheters and other medical equipment; their use could also be envisaged to confer biocidal properties to paints used in healthcare settings, or to air filters or face masks. Ag NPs loaded on filters show effective antiviral activity against bacteriophage MS2, which drops with dust loading.165\nThe antimicrobial activity of Cu has also been known since ancient times,166 and surfaces containing a significant amount of Cu have demonstrated their efficacy to inactivate viruses. Murray et al. showed the efficacy of Cu against poliovirus in 1979.167 More recently, the efficacy of Cu was demonstrated on the HuCoV-229E coronavirus; the effectiveness of Cu to inactivate other forms of coronaviruses suggests potential similar efficacy against SARS-CoV-2.168 Whereas HuCoV-229E persists for more than 6 days in an infectious state on smooth surfaces (Teflon, polyvinyl chloride, ceramic tiles, glass, stainless steel), it is inactivated in less than 60 min on brasses containing at least 70% Cu or Cu–Ni alloys containing at least 90% Cu.168 When incubated on Cu-containing surfaces, the viral genome becomes fragmented, ensuring the irreversibility of inactivation.168 The proposed inactivation mechanisms include both toxicity toward virions of Cu ions released from the Cu-containing surface and attack of viral proteins and lipids by ROS generated from Cu reacting with exogenous hydrogen or molecular oxygen through Fenton-like or Haber Weiss reactions.166 Likewise, both SARS-CoV-1 and SARS-CoV-2 are inactivated on Cu surfaces in less than 4 h, whereas they persist for 48–72 h on plastic and stainless steel and less than 24 h on cardboard.153 In this case, the main inactivation mechanism is also proposed to be damage to viral proteins and lipids by Cu ions and ROS, in particular, envelope proteins.153 Using Cu brasses or Cu-containing alloys rather than stainless steel would provide effective antimicrobial surfaces (doorknobs, bed rails, etc.) in healthcare settings. Supported catalysts composed of Al2O3 impregnated with Ag and Cu to form Ag/Al2O3 (5% Ag) and Cu/Al2O3 (10% Cu) also inactivate SARS-CoV virus in less than 5 and 20 min, respectively, which would be useful for air disinfection.169\nCu and CuO NPs have also been shown to release Cu ions when in contact with live cells.170,171 The large surface that NPs develop due to their small size endows them with a reactivity higher than that of their bulk counterpart and would fasten the kinetics of Cu ion release. The use of nanostructured Cu surfaces would further enhance their antimicrobial activity. Moreover, these NPs could inactivate viruses if sprayed on contaminated surfaces or loaded onto textile fabrics to confer antimicrobial properties (masks, blouses, etc.). Indeed, CuO-impregnated masks have shown remarkable anti-influenza virus (H1N1 and H9N2) activity under simulated breathing conditions,172 and the activity of these materials toward SARS-CoV-2 should be investigated. The viral disinfectant properties of Ag NPs and CuO NPs is further enhanced when they are combined with Fe as bimetallic particles, due to coupled redox reactions between the two metals.173\nIn addition to metal NPs, graphene derivatives have also shown promising viral inactivation properties.174 For example, graphene oxide (GO) sheets and sulfated GO derivatives have been found to be effective against herpes simplex virus type-1 (HSV-1) infections, with viral binding and shielding as the two putative main inhibitory mechanisms.175 Thermally reduced graphene oxide (rGO) sheets functionalized with biocompatible hyperbranched polyglycerol (hPG) and then sulfated have also been generated as graphene-based heparin biomimetics.176−178 Sulfate-rich polymers like heparan sulfate and its equivalent soluble counterpart heparin are widely known as broad antiviral agents,179,180 but their use is limited due to their anticoagulant effects. Sulfated rGO-hPG sheets were found to be effective at inhibiting orthopoxvirus and herpesvirus strains, particularly in the early stages of the infection, although they could not prevent cell-to-cell spread. Additional antiviral activity of graphene derivatives has been attributed to the negative surface charges and sharp edges of the individualized sheets, as the electrostatic interactions promote binding with the positively charged virus particles. Negative charges on sharp-edged single-sheet GO and rGO were shown to bind and to suppress the infection of pseudorabies, PEDV, EV71, and H9N2 viruses.181,182 This mechanism suggests that potentially similar antiviral effects could be offered by other negatively charged, sharp-edged 2D nanomaterials such as Ti3C2Tx MXene, which has shown promising bacterial inactivation effects against both Gram-positive and Gram-negative species due to similar hypothesized mechanisms.118,183\nGraphene derivatives linked to virus-specific antibodies have also been adopted in antiviral platforms based on antibody-mediated binding and sensing mechanisms, which have been shown to capture a number of viral species successfully including rotavirus, avian influenza virus subtypes H5 (AIV H5) and H7 (AIV H7), and influenza virus 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