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• W3136749291 abstract "Historically, emerging viruses appear constantly and have cost millions of human lives. Currently, climate change and intense globalization have created favorable conditions for viral transmission. Therefore, effective antivirals, especially those targeting the conserved protein in multiple unrelated viruses, such as the compounds targeting RNA-dependent RNA polymerase, are urgently needed to combat more emerging and re-emerging viruses in the future. Here we reviewed the development of antivirals with common targets, including those against the same protein across viruses, or the same viral function, to provide clues for development of antivirals for future epidemics. Historically, emerging viruses appear constantly and have cost millions of human lives. Currently, climate change and intense globalization have created favorable conditions for viral transmission. Therefore, effective antivirals, especially those targeting the conserved protein in multiple unrelated viruses, such as the compounds targeting RNA-dependent RNA polymerase, are urgently needed to combat more emerging and re-emerging viruses in the future. Here we reviewed the development of antivirals with common targets, including those against the same protein across viruses, or the same viral function, to provide clues for development of antivirals for future epidemics. The evolution of viruses has coincided with that of humans throughout history. The National Institute of Allergy and Infectious Diseases of the United States of America defines emerging viruses as those “that have newly appeared in a population or have existed but are rapidly increasing in incidence or geographic range.” Currently, eight viral diseases, including COVID-19, Ebola and Zika, are listed by WHO as prioritized diseases for research and development in emergency contexts (WHO, 2020WHOPrioritizing diseases for research and development in emergency contexts.2020Google Scholar). Notably, this list includes Disease X, which is caused by an unknown pathogen with potential to cause an epidemic across continents. In our modern history, the deadliest viral pandemic is the 1918 flu pandemic caused by influenza A virus (IAV) (Figure 1A), which infected about one-third of the world’s population and caused an estimated 50 million deaths (Morens and Fauci, 2020Morens D.M. Fauci A.S. Emerging Pandemic Diseases: How We Got to COVID-19.Cell. 2020; Abstract Full Text Full Text PDF Scopus (28) Google Scholar). IAVs are classified by the hemagglutinin (HA) and neuraminidase (NA) displayed on the viral envelope. The 1918-derived H1N1 influenza strains further circulated and evolved in human and pigs, resulting in the 1976 and 2009 H1N1 IAV outbreak. Moreover, the endemic epidemic of 1957 H2N2 and 1968 H3N2 IAV caused 2 million and 1 million fatalities, respectively. The abundant subtypes of influenza virus make it difficult to fully prevent and control. The second deadliest viral event in the modern era is the epidemic of human immunodeficiency virus (HIV) which has caused 35 million deaths since it was first recognized in 1981. As a retrovirus, the HIV genome will be reverse transcribed to DNA and integrated into host gene, thus persisting for a lifetime in patients and causing huge burden for patients, as well as public health systems (Cohn et al., 2020Cohn L.B. Chomont N. Deeks S.G. The Biology of the HIV-1 Latent Reservoir and Implications for Cure Strategies.Cell Host Microbe. 2020; 27: 519-530Abstract Full Text Full Text PDF PubMed Google Scholar). The COVID-19 pandemic is also considered “among the deadliest pandemics of the past century” (Morens and Fauci, 2020Morens D.M. Fauci A.S. Emerging Pandemic Diseases: How We Got to COVID-19.Cell. 2020; Abstract Full Text Full Text PDF Scopus (28) Google Scholar). As of December 18, 2020, confirmed cases of COVID-19 reached 75.5 million with 1.67 million deaths (https://covid19.who.int). The COVID-19 pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), belongs to the Betacoronavirus (β-CoV) genus and is a close relative of SARS-CoV and Middle East respiratory syndrome corona virus (MERS-CoV), which broke out in 2002 and 2012, respectively. These three coronavirus and HIV epidemics are considered as spillovers from animals. With more environmental perturbations by humans, such as deforestation, urbanization, and intensive animal hunting and trade, it can be speculated that more zoonotic viruses, i.e., those transmitted from animals to humans, may emerge. Another group of highly pathogenic viruses, hemorrhagic fever (HF)-associated viruses, did not cause numerous deaths globally, but did have high case fatality rates. Since it was first identified in 1976, Ebola virus (EBOV) disease has sporadically appeared in Africa with a fatality rate ranging from 25% to 90% (https://www.who.int/health-topics/ebola). Between 2014 and 2016, the EBOV epidemic ravaged West Africa with 28.6 thousand reported cases. HF-associated viruses from the Flaviviridae family, such as yellow fever, dengue, and West Nile virus, are a group of mosquito-borne viruses that have occasionally broken out around the world, especially in Africa and South America. In 2007, Zika virus (ZIKV), a virus from the Flaviviridae family, caused the first large outbreak in humans. ZIKV infection during pregnancy was found to be associated with microcephaly in infants, thus having elicited extensive public health concerns. Although our health infrastructure and knowledge in controlling infectious disease have advanced substantially, the past decade has still witnessed unprecedented viral epidemic explosion, including 2009 H1N1 IAV, 2012 MERS-CoV, 2014 EBOV, 2015 ZIKV, and 2019 SARS-COV-2. With changes in the environment and climate, we may confront more emerging and re-emerging virus epidemics. In this COVID-19 pandemic, the shortage of available and effective antivirals is taking a huge toll on human lives and social wealth. Before the next “Disease X” and global viral outbreak appear, we may be able to equip ourselves with more antivirals with common targets against highly pathogenic viruses. Although replication of different viruses varies, the viral life cycle has several common stages, including entry, biosynthesis, assembly, and release. Specifically, protein sequence and structure are highly similar among viruses from the same genus, as exemplified by the similar spike protein structure between SARS-CoV and SARS-CoV-2 (Wrapp et al., 2020Wrapp D. Wang N. Corbett K.S. Goldsmith J.A. Hsieh C.L. Abiona O. Graham B.S. McLellan J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.Science. 2020; 367: 1260-1263Crossref PubMed Scopus (9) Google Scholar). These similar processes and proteins usually serve as common targets for the development of antivirals. Viral entry, the initiation of viral infection, involves several sophisticated steps, wholly or partially including receptor recognition, surface protein priming, endocytosis, and membrane fusion (Figure 1B). Therefore, the receptor binding subunit on the viral surface, the cellular receptors, the cellular protease for protein priming, and the viral transmembrane subunit, which serves as membrane fusion machinery, are common therapeutic targets. After entry, the viral genome, DNA or RNA, is then released into cytoplasm or nuclei to serve as a template for the biosynthesis of structural or nonstructural proteins. The viral genome is simultaneously replicated and then assembled with viral proteins into a viral particle. In the replication process, RNA virus needs an RNA-dependent RNA or DNA polymerase (RdRp and RdDp), which is scarce in humans and, hence, a desirable antiviral target. In the assembly process, surface proteins (SPs) of the enveloped virus are expressed and insert into plasma membrane or endoplasmic reticulum. Viral particles are then coated by cell membranes and released to extracellular space through budding or cellular transportation pathway. Viral proteins, particularly the enveloped proteins, need post-translation modifications by viral protease before or after viral release, also comprising a target for antivirals. Here, we review the development of drugs for the above common targets against a bundle of representative highly pathogenic viruses, especially those that have caused pandemics in the last few decades, to provide some clues for the development of antiviral agents (Table 1) for future emerging viruses.Table 1Summary of antiviral agents targeting different sites in viral proteins under preclinical and clinical studiesAntiviral nameTypeTargetEffective spectrumDevelopmental stageCD4 mimetics (CD4-IgG2, 4Dm2m, 2DLT, etc.)ProteinViral RBDHIVCD4-IgG2: Phase I/IIRecombinant human ACE2ProteinViral RBDSARS-CoV, SARS-CoV-2Pilot clinical trialSialic acid-containing oligosaccharidesProteinViral RBDIAVPreclinicalFostemsavirSmall moleculeViral SfSHIVClinical drugFP-21399Small moleculeViral SfSHIV, SARS-CoVPhase INBD-11021 and NBD-14270Small moleculeViral RBDHIVPreclinicalMLS000078751 and MLS000534476Small moleculeViral SfSEBOV, MARVPreclinicalPyrimidines 2-12-2, 3-110-22Small moleculeViral SfSMost flaviviruses e.g., ZIKV, WNVPreclinicalOseltamivir, zanamivir, laninamivir octanoate,Small moleculeViral membrane proteinIAVClinical drugVRC01, 3BNC117, N6AntibodyViral RBDHIVPhase II and IREGN3048+REGN3051AntibodyViral RBDMERS-CoVPhase IREGN10933+REGN10987LY-CoV555AntibodyViral RBDSARS-CoV-2aAnti-SARS-CoV-2 antibodies are well reviewed in Renn et al., 2020.Emergency Use AuthorizationVHH-72, S309AntibodyViral RBDSARS-CoV-2aAnti-SARS-CoV-2 antibodies are well reviewed in Renn et al., 2020., SARS-COVPreclinicalVH3-23/VK1-5AntibodyViral RBDZIKV, DENVPreclinicalUB-421AntibodyRBD+receptorHIVPhase IIZMappAntibody cocktailSfS-TmS interfaceEBOVFailed in some clinical trials8ANC195, 35O22AntibodySfS-TmS interfaceHIVPreclinicalPGT121, 10-1074AntibodyOuter face of viral SfSHIVPhase II4A8, COV57AntibodyOuter face of viral SfSSARS-CoV-2PreclinicalREGN-EB3Antibody cocktailSfS-TmS interface, tip, and outer face of SfSEBOVApply for clinical approvalVIRIPPeptideFPHIVPhase IPF-68742Small moleculeFPHIVPreclinicalCA45, ADI-15878/15742AntibodyFPEBOVPreclinicalN123-VRC34.01AntibodyFPHIVPreclinicalSJ-2176, DP-178, C34, AlbuvirtidePeptideHR1HIVClinical drugCPT31PeptideHR1HIVPreclinicalCP1PeptideHR1SARS-CoVPreclinicalHR2PPeptideHR1MERS-CoVPreclinicalEK1, EK1C4PeptideHR1SARS-CoV-2, SARS-CoV, MERS-CoV, and 3 SARSr-CoVsPreclinicalIIS and IIYPeptideHR1MERS-CoV, IAVPreclinicalTat-EboPeptideHR1EBOV, MARVPreclinicalADS-J1, NB-2, NB-206Small moleculeHR1HIVPreclinicalUmifenovir (Arbidol)Small moleculeUnknownRSV, EBOV, HBV, HCVClinical drug for IAVTriterpenoidsSmall moleculeUnknownEBOV, MARV, HIV, IAVPreclinicalVIS410, MHAA4549A, MEDI8852, CR8020, CR6261AntibodyTmSIAVPhase IKZ50AntibodyTmSEBOVPreclinical2B2, 1A9, 4B12, IG10AntibodyTmSSARS-CoVPreclinical2F5, 4E10, Z13, 10E8, 10E8v2.0/iMabAntibodyMPERHIVPhase IBDBV223, BDBV317, BDBV340, ma-C10AntibodyHR2/MPEREBOVPreclinicalUruminPeptideMPER/CTIAVPreclinicalF9170PeptideCTHIVPreclinicalZ2PeptideMPER/CTZIKV, DENV-2, YFV 17DPreclinicalMaravirocSmall moleculeCCR5 (HIV coreceptor)HIVClinical drugIbalizumabAntibodyCD4 (HIV receptor)HIVClinical drugDAS181Small moleculesialic acid (IAV receptor)IAVPhase IISelective estrogen receptor modulators (SERMs)Small moleculeUnknownCoVs, HIV, HCV, EBOVClinical drug for nonviral diseaseCamostatSmall moleculeTMPRSS2CoVsClinical drug for nonviral diseaseTeicoplaninSmall moleculeCathepsin LCoVsClinical drug for nonviral diseaseApilimod and colchicineSmall moleculeEndocytosisCoVs, EBOVClinical drug for nonviral diseaseChloroquine (CQ) and hydroxychloroquine (HCQ)Small moleculeEndocytosis and other pathwaysFlaviviruses, retroviruses, CoVsClinical drug for nonviral diseaseRemdesivirSmall moleculeRdRpEBOV, SARS-CoV-2, MERS-CoV, etc.Emergency use authorization for SARS-CoV-2FavipiravirSmall moleculeRdRpRift Valley fever, Lassa, EBOV, ZIKV, etc.Clinical drug for influenza virusSofosbuvirSmall moleculeRdRpZIKV, DENV, SARS-CoV-2, etc.Clinical drug for HCVZidovudine, lamivudine, abacavir, TDFbAbbreviations: Phase I or II: Phase I or II clinical trial. TDF, tenofovir disoproxil fumarate; HIV, human immunodeficiency virus; SARS-CoV(−2), severe acute respiratory syndrome coronavirus (2); IAV, influenza A virus; HCV, hepatitis C virus; EBOV, Ebola virus; MARV, Marburg virus; ZIKV, Zika virus; WNV, West Nile virus; MERS-CoV, Middle East respiratory syndrome coronavirus; DENV, Dengue virus; SARSr-CoVs, SARS-CoV related virus; RSV, respiratory syncytial adenovirus; HBV, hepatitis B virus; YFV, Yellow fever virus., emtricitabineSmall moleculeRdDpHIV, HBV, etc.Clinical drug for HIVDoravirine, efavirenz, etravirine, nevirapine, rilpivirineSmall moleculeRdDpHIV, HBV, etc.Clinical drug for HIVRibavirinSmall moleculeRdDp and DdDpRSV, IAVs, Lassa virus, etc.Clinical drug for HCVSaquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, tipranavir, darunavirSmall moleculeProteaseHIVClinical drug for HIVMichael acceptors inhibitor N3, aldehydes, ketones, etacrynic acid derivatives, isatin compounds, GC376Small moleculeProteaseCoronavirusesPreclinicalDisulfiram, ebselen, boceprevir, telaprevir, simeprevir, paritaprevirSmall moleculeProteaseCoronavirusesDisulfiram and Ebselen: Phase II; others: clinical drug for HCVa Anti-SARS-CoV-2 antibodies are well reviewed in Renn et al., 2020Renn A. Fu Y. Hu X. Hall M.D. Simeonov A. Fruitful Neutralizing Antibody Pipeline Brings Hope To Defeat SARS-Cov-2.Trends Pharmacol Sci. 2020; Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar.b Abbreviations: Phase I or II: Phase I or II clinical trial. TDF, tenofovir disoproxil fumarate; HIV, human immunodeficiency virus; SARS-CoV(−2), severe acute respiratory syndrome coronavirus (2); IAV, influenza A virus; HCV, hepatitis C virus; EBOV, Ebola virus; MARV, Marburg virus; ZIKV, Zika virus; WNV, West Nile virus; MERS-CoV, Middle East respiratory syndrome coronavirus; DENV, Dengue virus; SARSr-CoVs, SARS-CoV related virus; RSV, respiratory syncytial adenovirus; HBV, hepatitis B virus; YFV, Yellow fever virus. Open table in a new tab In history, most emerging viruses are enveloped with class I fusion protein, which consists of surface subunit (SfS) and transmembrane subunit (TmS) (Figure 2). The SfS is responsible for viral binding to receptor, a process that can be competitively blocked by receptor mimetics. For example, soluble CD4, receptor of HIV, and recombinant proteins containing truncated CD4, such as CD4-IgG2, 4Dm2m, and 2DLT, are reported to inhibit HIV-1 infection in vitro (Su et al., 2020Su X. Wang Q. Wen Y. Jiang S. Lu L. Protein- and Peptide-Based Virus Inactivators: Inactivating Viruses Before Their Entry Into Cells.Front. Microbiol. 2020; 11: 1063Crossref PubMed Scopus (2) Google Scholar). Mono-administration of CD4-IgG2 reduced the viral loads in nine out of twelve HIV-infected individuals in a phase I/II clinical study (Jacobson et al., 2004Jacobson J.M. Israel R.J. Lowy I. Ostrow N.A. Vassilatos L.S. Barish M. Tran D.N. Sullivan B.M. Ketas T.J. O’Neill T.J. et al.Treatment of advanced human immunodeficiency virus type 1 disease with the viral entry inhibitor PRO 542.Antimicrob. Agents Chemother. 2004; 48: 423-429Crossref PubMed Scopus (0) Google Scholar). Proteins and peptides derived from angiotensin converting enzyme 2 (ACE2), the receptor for SARS-CoV and SARS-CoV-2, had potent cross-reactivity against both viruses in vitro (Curreli et al., 2020bCurreli F. Victor S.M.B. Ahmed S. Drelich A. Tong X. Tseng C.-T.K. Hillyer C.D. Debnath A.K. Stapled peptides based on Human Angiotensin-Converting Enzyme 2 (ACE2) potently inhibit SARS-CoV-2 infection in vitro.bioRxiv. 2020; (2020.2008.2025.266437)Google Scholar; Monteil et al., 2020Monteil V. Kwon H. Prado P. Hagelkruys A. Wimmer R.A. Stahl M. Leopoldi A. Garreta E. Hurtado Del Pozo C. Prosper F. et al.Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2.Cell. 2020; 181: 905-913.e907Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar). The safety of recombinant human ACE2 (rhACE2) in treating acute respiratory distress syndrome, a severe clinical symptom of coronavirus infection, was confirmed in a pilot clinical trial (Khan et al., 2017Khan A. Benthin C. Zeno B. Albertson T.E. Boyd J. Christie J.D. Hall R. Poirier G. Ronco J.J. Tidswell M. et al.A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome.Crit. Care. 2017; 21: 234Crossref PubMed Scopus (264) Google Scholar). Many sialic acid-containing oligosaccharides, the receptor for IAV, were also found to be effective in interfering with HA function and suppressing IAV replication (Sun, 2007Sun X.L. Recent anti-influenza strategies in multivalent sialyloligosaccharides and sialylmimetics approaches.Curr. Med. Chem. 2007; 14: 2304-2313Crossref PubMed Scopus (36) Google Scholar). Currently, no receptor-derived inhibitors have been approved for clinical use. Nonetheless, such inhibitors have the unparalleled advantage of high genetic barrier to viral escape. To account for this phenomenon, the virus that evolves resistance to the binding of receptor-derived agents may also fail to recognize the host receptor and thus cannot enter the target cell. However, they also potentially mediate viral entry into receptor-negative cells, as exemplified by sCD4-mediated HIV entry into CD4− cells. On the other hand, the receptor itself has physiological function in vivo as a host protein. That is, exogenous addition of a soluble receptor may accidently block, or activate, its ligand and normal functions, thus interfering with physiological signaling. In 2020, a first-in-class antiviral compound targeting HIV SfS, Rukobia (fostemsavir, BMS-663068), was licensed for HIV treatment. Rukobia, as well as other BMS-series compounds and FP-21399, can bind to prefusion HIV SfS and induce conformational change of the HIV envelope protein to prevent CD4 binding (Pancera et al., 2017Pancera M. Lai Y.T. Bylund T. Druz A. Narpala S. O’Dell S. Schön A. Bailer R.T. Chuang G.Y. Geng H. et al.Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529.Nat. Chem. Biol. 2017; 13: 1115-1122Crossref PubMed Scopus (45) Google Scholar). NBD-series compounds targeting HIV SfS, including NBD-11021 and NBD-14270, bind the receptor binding domain (RBD) on SfS directly to block binding between HIV and CD4 (Curreli et al., 2020aCurreli F. Ahmed S. Benedict Victor S.M. Iusupov I.R. Belov D.S. Markov P.O. Kurkin A.V. Altieri A. Debnath A.K. Preclinical Optimization of gp120 Entry Antagonists as anti-HIV-1 Agents with Improved Cytotoxicity and ADME Properties through Rational Design, Synthesis, and Antiviral Evaluation.J. Med. Chem. 2020; 63: 1724-1749Crossref PubMed Scopus (3) Google Scholar). MLS000078751 and MLS000534476 showed cross-inhibitory activity against Marburg and Ebola virus (MARV and EBOV) by targeting their respective SfS (Anantpadma et al., 2016Anantpadma M. Kouznetsova J. Wang H. Huang R. Kolokoltsov A. Guha R. Lindstrom A.R. Shtanko O. Simeonov A. Maloney D.J. et al.Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors.Antimicrob. Agents Chemother. 2016; 60: 4471-4481Crossref PubMed Scopus (35) Google Scholar). Although ZIKV is enveloped by class II fusion proteins, which are not divided into SfS and TmS, Yang’s group identified several compounds, such as pyrimidines 2-12-2 and 3-110-22, able to bind viral SP and inhibit infection of most flaviviruses, including Zika, West Nile, and Japanese encephalitis viruses (de Wispelaere et al., 2018de Wispelaere M. Lian W. Potisopon S. Li P.C. Jang J. Ficarro S.B. Clark M.J. Zhu X. Kaplan J.B. Pitts J.D. et al.Inhibition of Flaviviruses by Targeting a Conserved Pocket on the Viral Envelope Protein.Cell Chem Biol. 2018; 25: 1006-1016.e1008Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). Aside from the SP that mediates viral entry, some other proteins are expressed on the viral membrane, such as NA of influenza virus and M and E protein of coronavirus. NA inhibitors, oseltamivir, zanamivir, and laninamivir octanoate, which interfere with viral release from the host cell, have been approved for the treatment of influenza (Ikematsu and Kawai, 2011Ikematsu H. Kawai N. Laninamivir octanoate: a new long-acting neuraminidase inhibitor for the treatment of influenza.Expert Rev. Anti Infect. Ther. 2011; 9: 851-857Crossref PubMed Scopus (55) Google Scholar). Viral SfS is generally under high mutation pressure. As such, small-molecule inhibitors, as well as antibody-based inhibitors targeting the viral SfS, are difficult to develop into broad-spectrum drugs. However, at times, they are cross-effective to viruses from one genus. Therefore, in the case of a novel viral outbreak emergency, we need a system for rapid screening and safety evaluation of SfS-targeting antivirals. With antibody isolation and production technology advancing, the market for antibody-based drugs has been growing steadily in recent years. Antibodies have the advantages of high specificity, low immunogenicity, long half-life, as well as the ability to amplify host immune responses. However, activation of host immune response by antibody Fc signaling is a double-edged sword. It amplifies the antiviral signal but, meanwhile, may induce antibody-dependent enhancement (ADE) of viral infection or disease severity. Moreover, high specificity in combination with a variety of viral SfS is indicative of drug resistance. Therefore, the SfS- and TmS-targeting antibodies discussed below are typically used in cocktail therapy. Most antibodies against viral SfS in clinical trials are RBD-reactive, such as VRC01, 3BNC117, and N6 against HIV, Regeneron’s REGN3048 and REGN3051 against MERS-CoV, as well as several RBD-specific SARS-CoV-2 antibodies (Caskey et al., 2019Caskey M. Klein F. Nussenzweig M.C. Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic.Nat. Med. 2019; 25: 547-553Crossref PubMed Scopus (78) Google Scholar; Renn et al., 2020Renn A. Fu Y. Hu X. Hall M.D. Simeonov A. Fruitful Neutralizing Antibody Pipeline Brings Hope To Defeat SARS-Cov-2.Trends Pharmacol Sci. 2020; Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). For example, Regeneron’s REGN-COV2 and Lilly’s LY-CoV555, both of which are RBD-reactive, have been granted Emergency Use Authorization for COVID-19 by the U.S. FDA. Because SARS-CoV and SARS-CoV-2 have similar RBDs, several groups have found that SARS patient-derived antibodies targeting the RBD, such as VHH-72 and S309, could neutralize SARS-CoV-2, SARS-CoV, and SARS-related coronavirus (SARSr-CoV), suggesting the possibility of developing broad-spectrum antibodies to combat the current COVID-19 and future coronavirus disease outbreaks that may be caused by SARSr-CoVs (Renn et al., 2020Renn A. Fu Y. Hu X. Hall M.D. Simeonov A. Fruitful Neutralizing Antibody Pipeline Brings Hope To Defeat SARS-Cov-2.Trends Pharmacol Sci. 2020; Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). RBD of ZIKV, a class II fusion virus, can also be targeted by VH3-23/VK1-5 antibodies that are cross-reactive to ZIKV and dengue virus (DENV) (Robbiani et al., 2017Robbiani D.F. Bozzacco L. Keeffe J.R. Khouri R. Olsen P.C. Gazumyan A. Schaefer-Babajew D. Avila-Rios S. Nogueira L. Patel R. et al.Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico.Cell. 2017; 169: 597-609.e511Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Especially, the HIV antibody UB-421, which targets HIV RBD-receptor complex, maintained virologic suppression in patients when administered every 2 weeks in a phase II clinical trial (Wang et al., 2019Wang C.Y. Wong W.W. Tsai H.C. Chen Y.H. Kuo B.S. Lynn S. Blazkova J. Clarridge K.E. Su H.W. Lin C.Y. et al.Effect of Anti-CD4 Antibody UB-421 on HIV-1 Rebound after Treatment Interruption.N. Engl. J. Med. 2019; 380: 1535-1545Crossref PubMed Scopus (14) Google Scholar). These findings suggest that RBD-targeting antibodies are highly effective and sometimes cross-reactive to homogeneous virus. Because of the efficacy and specificity of RBD-specific antibodies, viral RBDs remain the most extensively investigated antigens in developing viral vaccine. Apart from the RBD, other common epitopes are found in viral SfS. ZMapp is renowned for its emergency application in treating Ebola patients when Ebola broke out in 2014. This bioproduct consists of three mouse–human chimeric antibodies targeting the SfS-TmS interface of EBOV (Hoenen et al., 2019Hoenen T. Groseth A. Feldmann H. Therapeutic strategies to target the Ebola virus life cycle.Nat. Rev. Microbiol. 2019; 17: 593-606Crossref PubMed Scopus (45) Google Scholar). However, a randomized trial revealed that ZMapp did not provide significant protection in vaccinated subjects (Davey et al., 2016Davey Jr., R.T. Dodd L. Proschan M.A. Neaton J. Neuhaus Nordwall J. Koopmeiners J.S. Beigel J. Tierney J. Lane H.C. Fauci A.S. et al.PREVAIL II Writing GroupMulti-National PREVAIL II Study TeamA Randomized, Controlled Trial of ZMapp for Ebola Virus Infection.N. Engl. J. Med. 2016; 375: 1448-1456Crossref PubMed Scopus (245) Google Scholar). The SfS-TmS interface of HIV can also be targeted by several potent bNAbs, including 8ANC195 (Figure 2) and 35O22 (Sok and Burton, 2018Sok D. Burton D.R. Recent progress in broadly neutralizing antibodies to HIV.Nat. Immunol. 2018; 19: 1179-1188Crossref PubMed Scopus (110) Google Scholar). The tip of viral SP is also an epitope that can be targeted by bNAb PG9 (Figure 2), PGDM1400 against HIV-1 (NCT03928821), and mAb114 against EBOV (Gaudinski et al., 2019Gaudinski M.R. Coates E.E. Novik L. Widge A. Houser K.V. Burch E. Holman L.A. Gordon I.J. Chen G.L. Carter C. et al.VRC 608 Study teamSafety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study.Lancet. 2019; 393: 889-898Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). Antibodies PGT121 and 10-1074, which both broadly inhibited HIV infection by binding to the outer face of HIV SfS, are under phase II clinical evaluation (Caskey et al., 2019Caskey M. Klein F. Nussenzweig M.C. Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic.Nat. Med. 2019; 25: 547-553Crossref PubMed Scopus (78) Google Scholar). The outer face of SfS of SARS-CoV-2 (also named NTD or S1A) can also be targeted by a couple of antibodies, such as 4A8 (Chi et al., 2020Chi X. Yan R. Zhang J. Zhang G. Zhang Y. Hao M. Zhang Z. Fan P. Dong Y. Yang Y. et al.A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2.Science. 2020; 369: 650-655Crossref PubMed Scopus (181) Google Scholar) and COV57 (Barnes et al., 2020Barnes C.O. West Jr., A.P. Huey-Tubman K.E. Hoffmann M.A.G. Sharaf N.G. Hoffman P.R. Koranda N. Gristick H.B. Gaebler C. Muecksch F. et al.Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies.Cell. 2020; Abstract Full Text Full Text PDF Scopus (4) Google Scholar) (Figure 2). Very recently, the FDA accepted for priority review a biologics license application for REGN-EB3, a mixture of three antibodies that target RBD, interface, and outer face of EBOV SfS, respectively, to treat Ebola disease (Mulangu et al., 2019Mulangu S. Dodd L.E. Davey Jr., R.T. Tshiani Mbaya O. Proschan M. Mukadi D. Lusakibanza Manzo M. Nzolo D. Tshomba Oloma A. Ibanda A. et al.PALM Writing GroupPALM Consortium Study TeamA Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.N. Engl. J. Med. 2019; 381: 2293-2303Crossref PubMed Scopus (501) Google Scholar). The TmS structure and function of class I fusion proteins are highly similar, and the TmS sequence is more conserved in homologous genus than that of SfS, making these proteins desirable targets for pan-genus virus inhibition. The TmS of class I fusion proteins is roughly divided into fusion peptide (FP), heptad repeat-1 (HR1), heptad repeat-2 (HR2), membrane proximal external region (MPER), transmembrane region (TM), and cytoplasmic tail (CT) (Figure 3A). FP of TmS is responsible for insertion into the host cell membrane (Mercer et al., 2020Mercer J. Lee J.E. Saphire E.O. Freeman S.A. SnapShot: Enveloped Virus Entry.Cell. 2020; 182: 786Abstract Full Text PDF PubMed Scopus (0) Google Scholar). Then, the HR1 interacts with homologous HR2, forming a stable six-helix bundle (6-HB) in which three HR2 helices pack in an antiparallel manner into the hydrophobic grooves on the HR1-trimer core. The 6-HB formation pulls viral and target cell membranes into close proximity for fusion (Figure 3B). FP, which serves as a viral anchor to host cell membrane, is substantially hydrophobic. Therefore, it is usually covered by the viral SfS in a prefusion conformation, limiting its accessibility as a drug target. Currently, FP-targeting inhibitors are few and mainly in the preclinical stages. Monotherapy of a peptide from α1-anti-trypsin (VIRIP), which targets the HIV FP, reduced the plasma viral load in treatment-naive, HIV-1-infected individuals (Forssmann et al., 2010Forssmann W.G. The Y.H. Stoll M. Adermann K. Albrecht U. Tillmann H.C. Barlos K. Busmann A. Canales-Mayordomo A. Giménez-Gallego G. et al.Short-term monotherapy in HIV-infected patients with a virus entry inhibitor against the gp41 fusion peptide.Sci. Transl. Med. 2010; 2: 63re3Crossref PubMed Scopus (61) Google Scholar). Compound PF-68742 and antibody N123-VRC34.01 against HIV and antibodies CA45," @default.
• W3136749291 created "2021-03-29" @default.
• W3136749291 creator A5013550923 @default.
• W3136749291 creator A5031109375 @default.
• W3136749291 creator A5053960511 @default.
• W3136749291 creator A5069302796 @default.
• W3136749291 date "2021-03-01" @default.
• W3136749291 modified "2023-10-12" @default.
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