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Id Subject Object Predicate Lexical cue
T1 0-97 Sentence denotes Widely available lysosome targeting agents should be considered as potential therapy for COVID-19
T2 100-110 Sentence denotes Highlights
T3 111-594 Sentence denotes • Lysosome targeting agents can disrupt endolysosomal maturation and inhibit viral replication • Lysosome targeting agents and lysosomotropic drugs should be explored as antiviral drugs for severe acute respiratory syndrome coronavirus-2 • Some lysosomotropic drugs are commonly used pharmacological agents • Particular attention should be directed towards macrolides (e.g. azithromycin), non-steroidal anti-inflammatory drugs (e.g. indomethacin) and other lysosomotoropic agents
T4 596-604 Sentence denotes Abstract
T5 605-746 Sentence denotes While the coronavirus disease 2019 (COVID-19) pandemic advances, the scientific community continues to struggle in the search for treatments.
T6 747-925 Sentence denotes Several improvements have been made, including discovery of the clinical efficacy of chloroquine (CQ) in patients with COVID-19, but effective treatment protocols remain elusive.
T7 926-1186 Sentence denotes In the search for novel treatment options, many scientists have used the in-silico approach to identify compounds that could interfere with the key molecules involved in entrance, replication or dissemination of severe acute respiratory syndrome coronavirus-2.
T8 1187-1352 Sentence denotes However, most of the identified molecules are not available as pharmacological agents at present, and assessment of their safety and efficacy could take many months.
T9 1353-1453 Sentence denotes This review took a different approach based on the proposed pharmacodynamic model of CQ in COVID-19.
T10 1454-1912 Sentence denotes The main mechanism of action responsible for the favourable outcome of patients with COVID-19 treated with CQ seems to be related to a pH-modulation-mediated effect on endolysosomal trafficking, a characteristic of chemical compounds often called ‘lysosomotropic agents’ because of the physico-chemical properties that enable them to diffuse passively through the endosomal membrane and undergo protonation-based trapping in the lumen of the acidic vesicles.
T11 1913-2090 Sentence denotes This review discusses lysosomotropic and lysosome targeting drugs that are already in clinical use and are characterized by good safety profiles, low cost and wide availability.
T12 2091-2424 Sentence denotes Some of these drugs –particularly azithromycin and other macrolides, indomethacin and some other non-steroidal anti-inflammatory drugs, proton pump inhibitors and fluoxetine – could provide additional therapeutic benefits in addition to the potential antiviral effect that is still to be confirmed by well-controlled clinical trials.
T13 2425-2782 Sentence denotes As some of these drugs have probably been used empirically in the treatment of COVID-19, it is hoped that colleagues worldwide will publish patient data to enable evaluation of the potential efficacy of these agents in the clinical context, and rapid implementation in therapeutic protocols if they are shown to have a beneficial effect on clinical outcome.
T14 2784-2799 Sentence denotes 1 Introduction
T15 2800-2928 Sentence denotes The main objective of all viruses is to hijack the intracellular machinery of the host cell for genome replication and assembly.
T16 2929-3006 Sentence denotes To achieve this, the virus first has to bypass the cellular membrane barrier.
T17 3007-3124 Sentence denotes The structure of some viruses enables direct fusion at the plasma membrane after recognition of the binding site [1].
T18 3125-3228 Sentence denotes However, most enveloped viruses depend on the endocytic pathway prior to fusion with the host cell [2].
T19 3229-3493 Sentence denotes Once endocytosis has been initiated, survival and replication of the virus depend on successful delivery of the viral nucleocapsid into the correct intracellular department, as different viral families target distinct compartments as primary replication sites [3].
T20 3494-3645 Sentence denotes Moreover, in order to survive, the virus has to escape from the endosomal compartment silently, without triggering the cellular defence mechanisms [4].
T21 3646-3787 Sentence denotes As a result, viral evolution involves highly complex escape strategies relying on different cues of endosomal maturation and trafficking [5].
T22 3788-4022 Sentence denotes Establishment of an acidic endosomal lumen is the key requirement for normal functioning of the endocytic pathway [6], so pH sensing has evolved as one of the fundamental strategies used by viruses to monitor endosomal maturation [7].
T23 4023-4268 Sentence denotes Two important sensing strategies are used by most viruses for induction of membrane fusion mechanisms: direct pH sensing mediated by a conformational change of the envelope glycoproteins, and endosomal protease-mediated proteolytic cleavage [7].
T24 4269-4355 Sentence denotes From a pharmacological perspective, this makes endosomal pH an attractive drug target.
T25 4356-4501 Sentence denotes Neutralization of endosomal pH obstructs endosomal trafficking, impedes sorting mechanisms, and inhibits activity of the endosomal proteases [6].
T26 4502-4650 Sentence denotes As a consequence, pharmacological modulation of endolysosomal pH could prevent viral fusion and impair the formation of viral replication complexes.
T27 4651-4787 Sentence denotes Moreover, as pH modulation is important for regulation of exocytosis, vesicular pH modulation could also affect viral dissemination [8].
T28 4788-4962 Sentence denotes Endosomal trafficking is necessary for normal cellular functioning, so long-term disruption of endosomal function could have considerable pathophysiological consequences [9].
T29 4963-5130 Sentence denotes Moreover, the infectivity of some viruses that use alternative strategies to enter the cell could be increased by pH-mediated inhibition of the endosomal pathway [10].
T30 5131-5285 Sentence denotes For this reason, most antiviral drug development strategies have focused on more specific fusion mechanisms rather than general inhibition of endocytosis.
T31 5286-5481 Sentence denotes However, short-term inhibition of endocytosis could be a viable strategy for the management of viral infections with no alternative treatment options, such as coronavirus disease 2019 (COVID-19).
T32 5482-5634 Sentence denotes Recent evidence suggests that chloroquine (CQ) and hydroxychloroquine (HCQ) may be effective therapeutic strategies for COVID-19 [11], [12], [13], [14].
T33 5635-5804 Sentence denotes Although the exact mechanism of action responsible for the antiviral activity of CQ and HCQ remains unclear, the elevation of lysosomal pH seems to play a key role [14].
T34 5805-5994 Sentence denotes This is in concordance with previous findings, as proteolytic processing of glycoprotein S by lysosomal proteases seems to be necessary for the fusion of coronavirus with the host cell [2].
T35 5995-6341 Sentence denotes Moreover, treatment of cells with glycoprotein S – the main protein responsible for viral fusion of severe acute respiratory syndrome coronavirus (SARS-CoV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) – resulted in translocation of the main viral receptor, angiotensin-converting enzyme 2 (ACE-2), to endosomal vesicles [15].
T36 6342-6488 Sentence denotes Furthermore, the same effect was demonstrated for spike-bearing pseudoviruses, emphasizing the importance of glycoprotein S for viral fusion [15].
T37 6489-6767 Sentence denotes It is important to mention that although many groups have demonstrated that SARS-CoV enters the cells by receptor-mediated, pH-sensitive endocytosis [15], some groups have reported that viral fusion might also occur by pH-independent direct fusion with the plasma membrane [16].
T38 6768-7161 Sentence denotes Although the exact mechanism responsible for the entrance of SARS-CoV-2 into the host cell remains to be elucidated, the authors believe that data from clinical trials on CQ and HCQ support the importance of pH-dependent endocytosis, and that other widely available pharmacological agents with lysosomotropic properties may also demonstrate clinical effectiveness in the treatment of COVID-19.
T39 7162-7355 Sentence denotes This review discusses commonly used pharmacological agents in the context of their lysosomotropic effects and pH-modulation-mediated interaction with cytoplasmic vesicle trafficking (Fig. 1 .).
T40 7356-7624 Sentence denotes Although almost 5 million people had been diagnosed with COVID-19 at the time of writing (20th May 2020), organized clinical data that would facilitate the evaluation of potential antiviral effects of the drugs discussed below on SARS-CoV-2 are unavailable at present.
T41 7625-7820 Sentence denotes Colleagues in possession of such data are urged to evaluate the possible benefits of these drugs, as they might offer new hope in terms of prevention and/or treatment of this devastating disease.
T42 7821-8004 Sentence denotes Fig. 1 Possible interaction of lysosomotropic agents and lysosome targeting drugs with the replication cycle of severe acute respiratory syndrome corovavirus-2 (SARS-CoV-2) in a cell.
T43 8005-8195 Sentence denotes Lysosome targeting drugs and lysosomotropic drugs, such as chloroquine, have the ability to interfere with endosomal trafficking, affecting both endosomal maturation and exocytotic pathways.
T44 8196-8488 Sentence denotes Taking into consideration the dependence of viral replication on the normal functioning of endocytic trafficking, commonly used pharmacological agents that demonstrate lysosomotropic properties should be examined as a possible therapeutic option for the treatment of coronavirus disease 2019.
T45 8490-8563 Sentence denotes 2 A brief introduction to the concept of lysosomotropism in pharmacology
T46 8564-8647 Sentence denotes The concept of lysosomotropism was first introduced by De Duve et al. in 1974 [17].
T47 8648-8785 Sentence denotes The term was originally proposed for all substances taken up by lysosomes, regardless of their chemical structure or mechanism of action.
T48 8786-8927 Sentence denotes Interestingly, the importance of the potential antiviral properties of lysosomotropic agents was emphasized in the original publication [17].
T49 8928-9176 Sentence denotes Moreover, some of the original concepts of lysosomotropism, such as the possibility to make virtually any substance lysosomotropic by suitable coupling with an appropriate chemical carrier, are now considered to be common principles in drug design.
T50 9177-9308 Sentence denotes In general, most substances with weakly basic and lipophilic properties are believed to demonstrate lysosomotropism to some extent.
T51 9309-9480 Sentence denotes These properties enable lysosomotropic drugs to diffuse passively through the endosomal membrane and undergo protonation-based trapping in the lumen of the acidic vesicle.
T52 9481-9805 Sentence denotes From a chemical standpoint, most drugs that demonstrate lysosomotropic properties are cationic substances that usually belong to the group of primary, secondary or tertiary amines; from a pharmacological point of view, these compounds are often described by very large volumes of distribution and long residual effects [18].
T53 9806-10005 Sentence denotes Moreover, lysosomotropic agents inhibit endosomal maturation and disrupt endolysosomal trafficking, and these effects are of particular interest in the context of viral infection, as described above.
T54 10006-10277 Sentence denotes The exact mechanisms by which different lysosomotropic agents induce these changes are still not well understood; however, modulation of pH and interaction with different molecular systems involved in pH regulation of endolysosomal vesicles seem to be the most important.
T55 10278-10418 Sentence denotes For deeper understanding of the current concept of lysosomotropism, the reader is referred to the informative review by Marceau et al. [18].
T56 10419-10666 Sentence denotes Antimalarial drugs, such as CQ, which have demonstrated clinical efficacy in the treatment of COVID-19 [11] are often referred to as classic lysosomotropic agents because their primary mechanism of action relies on their lysosomotropic properties.
T57 10667-10813 Sentence denotes CQ works by sequestration in digestive vacuoles that resemble endolysosomal compartments, and increases their pH to stop the nutrient supply [18].
T58 10814-11105 Sentence denotes Another interesting example of lysosomotropic pharmaceuticals are drugs used for the treatment of tuberculosis, where the drug has to reach both extracellular bacilli in the interstitial compartments and caseum, and intracellular pathogens residing in phagolysosomes of immune cells [18,19].
T59 11106-11384 Sentence denotes Consequently, retention of antituberculosis drugs in infected phagolysosomes has been considered an important factor in maximization of their efficiency [19], and this property has been investigated actively in the course of development of novel antituberculosis agents [20,21].
T60 11385-11667 Sentence denotes The importance of phagolysosomal sequestration of lysosomotropic agents in the context of Mycobacterium tuberculosis infection is also reflected by the fact that lysosomal neutralization with bafilomycin A or ammonium chloride inhibits the tuberculostatic effect of some drugs [22].
T61 11668-11916 Sentence denotes Interestingly, moderate antituberculosis activity has been shown in vitro for some standard lysosomotropic drugs, such as fluoxetine and sertraline, and this effect was absent in their non-protonable analogues that cannot undergo ion trapping [22].
T62 11917-12195 Sentence denotes However, apart from drugs that are well-known lysosomotropic substances, many pharmacological agents from other therapeutic classes belong to this group of chemicals based on both their physico-chemical properties and their effect on endolysosomal function in vitro and in vivo.
T63 12196-12440 Sentence denotes It is suggested that these drugs should be examined in the context of their potential use in COVID-19 treatment protocols, as most of them could potentially be used to target both viral replication and dissemination and symptoms of the disease.
T64 12441-12643 Sentence denotes Moreover, some drugs can produce similar effects on the endolysosomal pathway by targeting endosomal compartment pH through different mechanisms such as inhibition of vacuolar-type H+-ATPase (V-ATPase).
T65 12644-12760 Sentence denotes In the following text, these compounds are considered as potential candidate drugs with antiviral effects (Fig. 2 ).
T66 12761-13198 Sentence denotes As many pharmacological agents have shown endolysosomal pH-modulating activity both in vitro and in vivo, this review focused solely on drugs that satisfied several criteria that are considered important in this context: existing evidence of endolysosomal pH modulation, good safety profile, wide availability, low cost, and additional therapeutic benefits apart from the potential preventive and therapeutic antiviral effect (Table 1 ).
T67 13199-13507 Sentence denotes Fig. 2 Possible mechanisms of endolysosomal pH-modulation-mediated effects on the structure and function of endolysosomal vesicles with potential consequences for viral fusion, trafficking and shedding. (A) Drugs affecting activity of vesicular acidification mechanisms neutralize endolysosomal compartments.
T68 13508-14006 Sentence denotes The illustration shows the general structure of a proton pump inhibitor; this might neutralize endolysosomal compartments through inhibition of vacuolar-type H+-ATPase (V-ATPase). (B) Weakly basic and lipophilic properties of lysosomotropic compounds enable them to diffuse passively through the endosomal membrane and undergo protonation-based trapping and subsequent neutralization of acidic vesicles. (C) The acidic environment enables conformational changes that activate viral fusion proteins.
T69 14007-14336 Sentence denotes Moreover, H+ interacts with the viral matrix and activates mechanisms implicated in later stages of viral fusion and/or uncoating. (D) Acidic pH of endolysosomal compartments activates proteases involved with viral fusion processes. (E) The acidic luminal environment activates endolysosomal trafficking regulatory proteins [56].
T70 14337-14523 Sentence denotes Table 1 Drugs used in coronavirus disease 2019 (COVID-19) clinical trials with potential endolysosomal pH-mediated effect on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
T71 14524-14638 Sentence denotes Clinicaltrials.gov was searched for COVID-19, and pharmaceutical intervention data were analysed on 20th May 2020.
T72 14639-14711 Sentence denotes Both observational and interventional trials were included in the table.
T73 14713-14727 Sentence denotes 3 Antibiotics
T74 14728-14918 Sentence denotes Initial reports showed that more than 90% of patients with COVID-19 received antibiotics [24]; however, reports on how patient outcome depends on the use of different antibiotics are scarce.
T75 14919-15046 Sentence denotes Several groups of antibiotics are known to be lysosomotropic; however, the effect is observed most consistently for macrolides.
T76 15047-15278 Sentence denotes Therefore, this review will focus on macrolides as a potentially effective group of antibiotics in cases of COVID-19, as numerous studies have shown that macrolides possess anti-inflammatory, antibacterial and antiviral properties.
T77 15279-15586 Sentence denotes The anti-inflammatory effects [25] are of particular interest, as it has been suggested that a cytokine storm plays a central role in the development of acute respiratory distress syndrome following measurement of a high concentration of pro-inflammatory interleukins in the blood of deceased patients [26].
T78 15587-15757 Sentence denotes Another reason to consider macrolides is their antiviral effect, particularly for, but not limited to, clarithromycin, bafilomycin, erythromycin and azithromycin [27,28].
T79 15758-15928 Sentence denotes Although the effects of macrolides on the expression of cytokines and membrane receptors contribute to the antiviral effects, the exact mechanism remains unknown [27,28].
T80 15929-16182 Sentence denotes As several authors have reported that macrolides can affect lysosomal trafficking and lysosomal pH [29,30], it is hypothesized that this could be one of several mechanisms of antiviral activity of macrolides, and is particularly interesting in COVID-19.
T81 16183-16343 Sentence denotes Although the antiviral effects of macrolides have been known for a long time, the use of these drugs in patients has not yielded groundbreaking results [27,31].
T82 16344-16525 Sentence denotes Although early clinical findings suggested the effectiveness of azithromycin in combination with HCQ [32], some recent observations have challenged the original conclusions [33,34].
T83 16526-16675 Sentence denotes Thus, well-controlled, randomized, large-scale clinical trials are needed to draw conclusions regarding the use of azithromycin for COVID-19 [34,35].
T84 16676-16901 Sentence denotes Hopefully, the 60 ongoing clinical trials listed on clinicaltrials.gov with azithromycin included in the interventional design will provide sufficient evidence to settle the ongoing debate on its potential effectiveness [23].
T85 16902-17194 Sentence denotes Apart from the potential antiviral and anti-inflammatory potential, other very important properties of macrolides should be mentioned, namely their ability to inhibit the proliferation of fibroblasts, production of collagen, and release of matrix protease and pro-inflammatory cytokines [36].
T86 17195-17377 Sentence denotes These are particularly interesting and important properties of macrolides in the context of long-term consequences, as it has been debated that COVID-19 may cause lung fibrosis [37].
T87 17378-17728 Sentence denotes Considering everything mentioned above and the recent in-silico finding that clarithromycin and erythromycin could have a direct antiviral effect by interfering with COVID-19 protease [38], macrolides should be investigated further as a treatment option, including the route of administration, with inhalatory macrolides being of particular interest.
T88 17729-17812 Sentence denotes Unfortunately, inhalatory macrolides are not available for clinical use at present.
T89 17813-18097 Sentence denotes The physico-chemical properties of these drugs suggest that they are suitable for aerosolization, and in-vivo experiments have demonstrated that inhalation leads to a rapid increase in concentration in alveolar macrophages and airway epithelial cells in the case of azithromycin [36].
T90 18099-18139 Sentence denotes 4 Non-steroidal anti-inflammatory drugs
T91 18140-18316 Sentence denotes The safety of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with COVID-19 has been debated since the discovery that ACE-2 is an entry receptor for SARS-CoV-2 [39].
T92 18317-18491 Sentence denotes Fang et al. hypothesized that ibuprofen increases the risk of developing severe and fatal COVID-19 as it is known that it can increase the expression of ACE-2 receptors [40].
T93 18492-18652 Sentence denotes However, this has not been supported by any clinical study, and cannot be confirmed post hoc given the common practice of not making raw patient data available.
T94 18653-18906 Sentence denotes Nevertheless, taking into account the above-mentioned relationship between endosomal trafficking and viral replication, NSAIDs could provide additional benefits in the treatment of COVID-19 as a result of their inhibitory effect on autophagic flux [41].
T95 18907-18964 Sentence denotes Indomethacin is particularly interesting in this context.
T96 18965-19051 Sentence denotes Several studies have shown that indomethacin can increase the pH of lysosomes [41,42].
T97 19052-19302 Sentence denotes Moreover, some results have suggested that indomethacin can block viral RNA synthesis independently of its effect on cyclo-oxygenase inhibition, and this effect was confirmed both in vitro and in vivo on dogs infected with canine coronavirus [43,44].
T98 19303-19491 Sentence denotes Furthermore, it has been shown that indomethacin enhances the inhibitory effect of CQ on autophagy, suggesting that NSAIDs and CQ could have a synergistic effect on viral replication [42].
T99 19492-19868 Sentence denotes In conclusion, at this point, there are not enough studies to demystify the potential role of NSAIDs in COVID-19; however, in addition to standard anti-inflammatory and antipyretic properties, other factors should be taken into account, such as the possible effect of NSAIDs on the expression of ACE-2, interference with autophagic flux and possible direct antiviral activity.
T100 19869-20105 Sentence denotes The authors believe that more attention should be directed towards these potential effects, and structured clinical data should be collected in order to examine if some NSAIDs should be considered better than others for this indication.
T101 20107-20132 Sentence denotes 5 Proton pump inhibitors
T102 20133-20234 Sentence denotes To alleviate the side-effects of NSAIDs, proton pump inhibitors (PPIs) are often given concomitantly.
T103 20235-20347 Sentence denotes It is important to note that PPIs can inhibit V-ATP-ase, the enzyme responsible for maintaining pH in endosomes.
T104 20348-20457 Sentence denotes As a consequence, PPIs can induce cytosolic acidification and lysosomal and endosomal alkalinization [45,46].
T105 20458-20536 Sentence denotes As discussed above, this effect could be beneficial in patients with COVID-19.
T106 20537-20798 Sentence denotes In the context of the direct and indirect antiviral effects of indomethacin discussed above, and its well-known gastrointestinal side-effects, a combination of indomethacin and PPIs should be investigated further as a potential therapeutic strategy in COVID-19.
T107 20799-21104 Sentence denotes Additionally, ACE-2, which acts as a primary receptor for SARS-CoV-2 host cell entry, is a well-known intestinal transporter involved in amino acid absorption throughout the human small intestine [47], and gastrointestinal symptoms are reported to be part of the clinical presentation of COVID-19 [48,49].
T108 21105-21269 Sentence denotes Therefore, targeting the gastrointestinal system could have a dual benefit as lysosomotropic agents could provide symptomatic relief and reduce viral dissemination.
T109 21270-21674 Sentence denotes The possibility that the faecal-oral transmission route is involved in viral spread, in combination with the recent finding that viral RNA remained positive in faeces even after negative conversion of viral RNA in the respiratory system, further supports the idea that lysosomotropic agents that primarily target the gastrointestinal system should be considered as part of the treatment of COVID-19 [48].
T110 21676-21719 Sentence denotes 6 Selective serotonin re-uptake inhibitors
T111 21720-21785 Sentence denotes Many central nervous system drugs have lysosomotropic properties.
T112 21786-22053 Sentence denotes Some lysosomotropic compounds used in experimental work on endolysosomal trafficking and function include the tricyclic antidepressants, imipramine and amitriptyline; the antipsychotic, chlorpromazine; and the selective serotonin re-uptake inhibitor, fluoxetine [50].
T113 22054-22256 Sentence denotes If further research provides clinical evidence for the antiviral effect of fluoxetine, it could be considered as part of the solution in addition to virtual psychotherapy for quarantine-induced anxiety.
T114 22257-22586 Sentence denotes This might be more important than it seems, as findings published after the previous SARS epidemic suggest that the psychological effects of quarantine are underestimated [51], [52], [53], and the rapid response of psychologists and psychiatrists during the ongoing pandemic confirms that early intervention is important [54,55].
T115 22587-22814 Sentence denotes Moreover, maximal compliance is needed to implement successful quarantine and social isolation measures, and considering the information in the global media, anxiolysis is more important than ever in order to stop viral spread.
T116 22816-22829 Sentence denotes 7 Conclusion
T117 22830-23131 Sentence denotes In conclusion, many pharmacological agents that are widely used in clinical practice demonstrate endolysosomal pH-modulating properties both in vitro and in vivo, and should thus be considered as potential therapeutic agents for COVID-19 in light of the recent findings on the clinical efficacy of CQ.
T118 23132-23326 Sentence denotes Most of the drugs discussed in this review have good safety profiles, low cost and are widely available, which makes them interesting in the context of the rapidly advancing SARS-CoV-2 pandemic.
T119 23327-23543 Sentence denotes As some of these drugs have probably been used empirically in the treatment of COVID-19, it is hoped that colleagues worldwide will publish patient data to enable evaluation of the potential efficacy of these agents.
T120 23544-23793 Sentence denotes As effective treatment strategies for COVID-19 are still lacking, repurposing of drugs based on their lysosomotropic and endolysosomal pH-modulating effects could provide the additional preventive and therapeutic options that are desperately needed.