Current progress in antiviral strategies
2014; Elsevier BV; Volume: 35; Issue: 2 Linguagem: Inglês
10.1016/j.tips.2013.11.006
ISSN1873-3735
AutoresZhiyong Lou, Yuna Sun, Zihe Rao,
Tópico(s)Hepatitis C virus research
Resumo•Antiviral agents function as either viral targets or host factors.•Virus-targeting antivirals (VTAs) function through a direct (DVTAs) or an indirect (InDVTAs) method in the viral life cycle.•Host-targeting antivirals (HTAs) include reagents that target the host proteins that are involved in the viral life cycle. The prevalence of chronic viral infectious diseases, such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza virus; the emergence and re-emergence of new viral infections, such as picornaviruses and coronaviruses; and, particularly, resistance to currently used antiviral drugs have led to increased demand for new antiviral strategies and reagents. Increased understanding of the molecular mechanisms of viral infection has provided great potential for the discovery of new antiviral agents that target viral proteins or host factors. Virus-targeting antivirals can function directly or indirectly to inhibit the biological functions of viral proteins, mostly enzymatic activities, or to block viral replication machinery. Host-targeting antivirals target the host proteins that are involved in the viral life cycle, regulating the function of the immune system or other cellular processes in host cells. Here we review key targets and considerations for the development of both antiviral strategies. The prevalence of chronic viral infectious diseases, such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza virus; the emergence and re-emergence of new viral infections, such as picornaviruses and coronaviruses; and, particularly, resistance to currently used antiviral drugs have led to increased demand for new antiviral strategies and reagents. Increased understanding of the molecular mechanisms of viral infection has provided great potential for the discovery of new antiviral agents that target viral proteins or host factors. Virus-targeting antivirals can function directly or indirectly to inhibit the biological functions of viral proteins, mostly enzymatic activities, or to block viral replication machinery. Host-targeting antivirals target the host proteins that are involved in the viral life cycle, regulating the function of the immune system or other cellular processes in host cells. Here we review key targets and considerations for the development of both antiviral strategies. Viruses comprise a large group of pathogens that are responsible for causing severe infectious diseases. Over the past 30 years, antiviral agents that target viral proteins or host factors have been successfully developed. Based on their inhibitory mechanisms, antiviral reagents can be divided into two groups: (i) inhibitors that target the viruses themselves or (ii) inhibitors that target host cell factors. Virus-targeting antivirals (VTAs) can function directly (DVTAs) or indirectly (InDVTAs) to inhibit biological functions of viral proteins, mostly enzymatic activities, or they block the correct formation of the viral replication machinery (Table 1). Host-targeting antivirals (HTAs) include reagents that target the host proteins that are involved in the viral life cycle (Figure 1), regulating the function of the immune system or other cellular processes in host cells. With increased knowledge of viral protein and host factors, the scientific community has achieved great progress in mechanism-based antiviral discovery against chronic viral infectious diseases, and in understanding of the emergence of new viral diseases and of the resistance to traditional antivirals. This review will highlight recent achievements in antiviral development and discuss various strategies for preventing virus attachment and entry into the host cell, as well as strategies for preventing virus replication and transcription within the host cell.Table 1A summary of the antivirals described in this reviewGroupSubgroupNameStructure formulaTarget and mechanismDirect virus-targeting antivirals (DVTAs)Attachment inhibitorsBMS488043Block HIV-1 gp120–CD4 interactionBMS663068ICAM-1Block HRV–receptor interactionOseltamivirInfluenza NAIZanamivirLaninamivirPeramivirEntry inhibitorsT20 peptide (Enfuvirtide)YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFBlock the conformational changes of HIV-1 gp41Cp32MVEWNEMTWMEWEREIENYTKLIYKILESSQEQSifuvirtideSWETWEREIENYTRQIYRILEESQEQQDRNERDLLET2635TTWEAWDRAIAEYAARIEALIRAAQEQQEKNEAALRELPleconarilReplace the natural pocket factor and inhibit picornaviral uncoatingBTA798Protease inhibitorsAmprenavirHIV-1 PIsAtazanavirDarunavirFosamprenavirIndinavirLopinavirNelfinavirRitonavirSaquinavirTipranavirPolymerase inhibitorsZidovudine (AZT)HIV-1 NRTIDidanosine (ddi)Zalcitabine (ddC)Stavudine (d4T)Lamivudine (3TC)NevirapineHIV-1 NNRTIDelavirdineEfavirenzEtravirineRilpivirineIntegrase inhibitorsRaltegravirIntegrase strand transfer inhibitor (INSTI)DolutegravirElvitegravir (Stribild)Methyltransferase inhibitorsAurintricarboxylic acidInhibit the 2′-O activity of DENV MTaseSinefunginAn analog of SAM that inhibits the activity of flavivirus MTaseBG323Inhibit the guanylyltransferase activity of DENV MTaseHelicase inhibitorsBiphenylsInhibit HPV E1 helicase activityBiphenysulfonacetic acidTriclocarban (CID 7547)Inhibit SV40 Tag helicase activityBisphenol A (BPA; CID 6623)Triphenylmethanes (CID 42618092)Inhibit HCV NS3 helicase activityAurintricarboxylic acid (ATA)Indirect virus-targeting antivirals (InDVTAs)RTC blockersBMS790052Inhibit the hyperphosphorylation of NS5ARNP blockersNucleozinInhibit the nuclear accumulation of influenza NPThe first 25 amino acids of PB1GPLGSMDVNPTLLFLKVPAQNAISTTFPYTInhibit the interaction of PA-PB1 and influenza polymerase activitySuraminBind to the RNA-binding cavity and inhibit SFTSV replicationOthersCHEMBL1207308Inhibit the interaction of HPV E1–E2Host-targeting antivirals (HTAs)Cyclophilin inhibitorsAlisporivir (Debio-025)Inhibit the function of cyclophilinsNIM811SCY635HIV-1 co-receptor antagonistsAplavirocCCR5 antagonistMaravirocVicrivirocCenicriviroc Open table in a new tab The first step in viral invasion is the attachment to host cells via an interaction with functional receptor(s). For enveloped viruses, the viral proteins located on the outer envelope of the virion are responsible for the recognition of receptors and the attachment to host cells. HIV (a member of the Retroviridae family) is a typical enveloped virus, and its invasion is mediated by the envelope proteins gp120 and gp41, which are arranged on the viral membrane as a trimer of three trans-membrane gp41 and three noncovalently attached gp120 surface subunits [1Mao Y. et al.Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer.Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 12438-12443Crossref PubMed Scopus (14) Google Scholar] (Figure 2). gp120 recognizes the CD4 receptor and launches the conformational changes that expose the binding sites for the binding of a co-receptor, (i.e., CCR5 and CXCR4 [2Georgiev I.S. et al.Elicitation of HIV-1-neutralizing antibodies against the CD4-binding site.Curr. Opin. HIV AIDS. 2013; 8: 382-391Crossref PubMed Scopus (1) Google Scholar]). 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Moreover, laninamivir and peramivir were also approved in North Asia recently. Laninamivir has excellent in vitro activity against wild type, as well as oseltamivir-resistant, influenza viruses currently circulating [12Yamashita M. Laninamivir and its prodrug, CS-8958: long-acting neuraminidase inhibitors for the treatment of influenza.Antivir. Chem. Chemother. 2010; 21: 71-84Crossref PubMed Scopus (30) Google Scholar]. Additionally, peramivir is another NAI that differs structurally from other inhibitors through novel substitutions that result in multiple binding interactions with the active site and allows the antiviral to be active against NAI-resistant viruses [13Hernandez J.E. et al.Clinical experience in adults and children treated with intravenous peramivir for 2009 influenza A (H1N1) under an Emergency IND program in the United States.Clin. Infect. Dis. 2011; 52: 695-706Crossref PubMed Scopus (39) Google Scholar]. 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Because this viral entry is one of the key early steps in the viral life cycle (Figure 1), entry inhibitors have been successfully developed for antiviral therapies. As an enveloped virus, HIV-1 uses gp41 to facilitate its entry process after gp41 is activated by the binding of gp120 to the receptor. The extracellular portion of gp41 contains two heptad repeat domains (HR1 and HR2) separated by a loop region and a hydrophobic fusion peptide (FP) at the N terminus. During the fusion process, the FP of gp41 is inserted into the host cell membrane, and HR1 adopts a triple-stranded coiled-coil structure, forming a meta-stable prefusion intermediate. HR2 subsequently folds into the hydrophobic grooves of the HR1 coiled-coil to form a stable six-helix bundle that juxtaposes the viral and cellular membranes for fusion (Figure 2C). Fusion inhibitors are designed to block the conformational changes that are required for membrane fusion. 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