Antiviral Drug Targets of Single-Stranded RNA Viruses Causing Chronic Human Diseases

Author(s): Dhurvas Chandrasekaran Dinesh*, Selvaraj Tamilarasan, Kaushik Rajaram, Evžen Bouřa*

Journal Name: Current Drug Targets

Volume 21 , Issue 2 , 2020

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Graphical Abstract:


Ribonucleic acid (RNA) viruses associated with chronic diseases in humans are major threats to public health causing high mortality globally. The high mutation rate of RNA viruses helps them to escape the immune response and also is responsible for the development of drug resistance. Chronic infections caused by human immunodeficiency virus (HIV) and hepatitis viruses (HBV and HCV) lead to acquired immunodeficiency syndrome (AIDS) and hepatocellular carcinoma respectively, which are one of the major causes of human deaths. Effective preventative measures to limit chronic and re-emerging viral infections are absolutely necessary. Each class of antiviral agents targets a specific stage in the viral life cycle and inhibits them from its development and proliferation. Most often, antiviral drugs target a specific viral protein, therefore only a few broad-spectrum drugs are available. This review will be focused on the selected viral target proteins of pathogenic viruses containing single-stranded (ss) RNA genome that causes chronic infections in humans (e.g. HIV, HCV, Flaviviruses). In the recent past, an exponential increase in the number of available three-dimensional protein structures (>150000 in Protein Data Bank), allowed us to better understand the molecular mechanism of action of protein targets and antivirals. Advancements in the in silico approaches paved the way to design and develop several novels, highly specific small-molecule inhibitors targeting the viral proteins.

Keywords: RNA viruses, chronic diseases, drug targets, inhibitors, antivirals, HIV, hepatitis, flaviviruses, protein structures.

De Clercq E, Li G. Approved antiviral drugs over the past 50 years. Clin Microbiol Rev 2016; 29(3): 695-747.
[] [PMID: 27281742]
McCarthy MK, Morrison TE. Persistent RNA virus infections: do PAMPS drive chronic disease? Curr Opin Virol 2017; 23: 8-15.
[] [PMID: 28214732]
Randall RE, Griffin DE. Within host RNA virus persistence: mechanisms and consequences. Curr Opin Virol 2017; 23: 35-42.
[] [PMID: 28319790]
Schlabe S, Rockstroh JK. Advances in the treatment of HIV/HCV coinfection in adults. Expert Opin Pharmacother 2018; 19(1): 49-64.
[] [PMID: 29252031]
Zuniga EI, Macal M, Lewis GM, Harker JA. Innate and adaptive immune regulation during chronic viral infections. Annu Rev Virol 2015; 2(1): 573-97.
[] [PMID: 26958929]
Duffy S. Why are RNA virus mutation rates so damn high? PLoS Biol 2018; 16(8) e3000003
[] [PMID: 30102691]
Mason S, Devincenzo JP, Toovey S, Wu JZ, Whitley RJ. Comparison of antiviral resistance across acute and chronic viral infections. Antiviral Res 2018; 158: 103-12.
[] [PMID: 30086337]
Chu C, Pollock LC, Selwyn PA. HIV-associated complications: A systems-based approach. Am Fam Physician 2017; 96(3): 161-9.
[PMID: 28762691]
Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules 2015; 20(7): 13384-421.
[] [PMID: 26205061]
van Montfort RLM, Workman P. Structure-based drug design: aiming for a perfect fit. Essays Biochem 2017; 61(5): 431-7.
[] [PMID: 29118091]
Engelman A, Cherepanov P. The structural biology of HIV-1: mechanistic and therapeutic insights. Nat Rev Microbiol 2012; 10(4): 279-90.
[] [PMID: 22421880]
Wain-Hobson S, Sonigo P, Danos O, Cole S, Alizon M. Nucleotide sequence of the AIDS virus, LAV. Cell 1985; 40(1): 9-17.
[] [PMID: 2981635]
Li G, De Clercq E. HIV Genome-wide protein associations: A review of 30 years of research. Microbiol Mol Biol Rev 2016; 80(3): 679-731.
[] [PMID: 27357278]
Human Immunodeficiency Virus (HIV). Transfus Med Hemother 2016; 43(3): 203-22.
[] [PMID: 27403093]
Barré-Sinoussi F, Ross AL, Delfraissy JF. Past, present and future: 30 years of HIV research. Nat Rev Microbiol 2013; 11(12): 877-83.
[] [PMID: 24162027]
Zhan P, Pannecouque C, De Clercq E, Liu X. Anti-HIV Drug discovery and development: Current innovations and future trends. J Med Chem 2016; 59(7): 2849-78.
[] [PMID: 26509831]
Rai MA, Pannek S, Fichtenbaum CJ. Emerging reverse transcriptase inhibitors for HIV-1 infection. Expert Opin Emerg Drugs 2018; 23(2): 149-57.
[] [PMID: 29737220]
Jayappa KD, Ao Z, Yao X. The HIV-1 passage from cytoplasm to nucleus: the process involving a complex exchange between the components of HIV-1 and cellular machinery to access nucleus and successful integration. Int J Biochem Mol Biol 2012; 3(1): 70-85.
[PMID: 22509482]
Isel C, Ehresmann C, Keith G, Ehresmann B, Marquet R. Initiation of reverse transcription of HIV-1: secondary structure of the HIV-1 RNA/tRNA(3Lys) (template/primer). J Mol Biol 1995; 247(2): 236-50.
[] [PMID: 7707372]
Rhim H, Park J, Morrow CD. Deletions in the tRNA(Lys) primer-binding site of human immunodeficiency virus type 1 identify essential regions for reverse transcription. J Virol 1991; 65(9): 4555-64.
[PMID: 1714513]
Larsen KP, Mathiharan YK, Kappel K, et al. Architecture of an HIV-1 reverse transcriptase initiation complex. Nature 2018; 557(7703): 118-22.
[] [PMID: 29695867]
Coey AT, Larsen KP, Choi J, Barrero DJ, Puglisi JD, Puglisi EV. Dynamic interplay of RNA and protein in the human immunodeficiency virus-1 reverse transcription initiation complex. J Mol Biol 2018; 430(24): 5137-50.
[] [PMID: 30201267]
Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA. Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 1992; 256(5065): 1783-90.
[] [PMID: 1377403]
Jacobo-Molina A, Ding J, Nanni RG, et al. Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA. Proc Natl Acad Sci USA 1993; 90(13): 6320-4.
[] [PMID: 7687065]
Hu WS, Hughes SH. HIV-1 reverse transcription. Cold Spring Harb Perspect Med 2012; 2(10)a006882
[] [PMID: 23028129]
Das K, Martinez SE, Bauman JD, Arnold E. HIV-1 reverse transcriptase complex with DNA and nevirapine reveals non-nucleoside inhibition mechanism. Nat Struct Mol Biol 2012; 19(2): 253-9.
[] [PMID: 22266819]
Das K, Martinez SE, DeStefano JJ, Arnold E. Structure of HIV-1 RT/dsRNA initiation complex prior to nucleotide incorporation. Proc Natl Acad Sci USA 2019; 116(15): 7308-13.
[] [PMID: 30902895]
Yang Y, Kang D, Nguyen LA, et al. Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors. eLife 2018; 7: 7.
[] [PMID: 30044217]
Esbjörnsson J, Månsson F, Kvist A, et al. Long-term follow-up of HIV-2-related AIDS and mortality in Guinea-Bissau: a prospective open cohort study. Lancet HIV 2018; S2352-3018(18): 30254-6.
[PMID: 30392769]
Gu WG, Zhang X, Yuan JF. Anti-HIV drug development through computational methods. AAPS J 2014; 16(4): 674-80.
[] [PMID: 24760437]
Soltani A, Hashemy SI, Zahedi Avval F, et al. Molecular targeting for treatment of human T-lymphotropic virus type 1 infection. Biomed Pharmacother 2019; 109: 770-8.
[] [PMID: 30551530]
Zanella L, Otsuki K, Marin MA, Bendet I, Vicente AC. Complete genome sequence of Central Africa human T-cell lymphotropic virus subtype 1b. J Virol 2012; 86(22): 12451.
[] [PMID: 23087114]
Lavorgna A, Harhaj EW. Regulation of HTLV-1 tax stability, cellular trafficking and NF-κB activation by the ubiquitin-proteasome pathway. Viruses 2014; 6(10): 3925-43.
[] [PMID: 25341660]
Marino-Merlo F, Mastino A, Grelli S, Hermine O, Bazarbachi A, Macchi B. Future perspectives on drug targeting in adult T cell leukemia-lymphoma. Front Microbiol 2018; 9: 925.
[] [PMID: 29867836]
Carrillo-Infante C, Abbadessa G, Bagella L, Giordano A. Viral infections as a cause of cancer (review). Int J Oncol 2007; 30(6): 1521-8.
[] [PMID: 17487374]
Jinno-Oue A, Tanaka A, Shimizu N, et al. Inhibitory effect of chondroitin sulfate type E on the binding step of human T-cell leukemia virus type 1. AIDS Res Hum Retroviruses 2013; 29(3): 621-9.
[] [PMID: 23033806]
Kuhnert M, Steuber H, Diederich WE. Structural basis for HTLV-1 protease inhibition by the HIV-1 protease inhibitor indinavir. J Med Chem 2014; 57(14): 6266-72.
[] [PMID: 25006983]
Bukh J. The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control. J Hepatol 2016; 65(1)(Suppl.): S2-S21.
[] [PMID: 27641985]
Pirakitikulr N, Kohlway A, Lindenbach BD, Pyle AM. The coding region of the hcv genome contains a network of regulatory rna structures. Mol Cell 2016; 62(1): 111-20.
[] [PMID: 26924328]
Axley P, Ahmed Z, Ravi S, Singal AK, Hepatitis C. Hepatitis C virus and hepatocellular carcinoma: A Narrative Review. J Clin Transl Hepatol 2018; 6(1): 79-84.
[] [PMID: 29607308]
Atoom AM, Taylor NG, Russell RS. The elusive function of the hepatitis C virus p7 protein. Virology 2014; 462-463: 377-87.
[] [PMID: 25001174]
Mitchell JK, Lemon SM, McGivern DR. How do persistent infections with hepatitis C virus cause liver cancer? Curr Opin Virol 2015; 14: 101-8.
[] [PMID: 26426687]
McGivern DR, Masaki T, Lovell W, Hamlett C, Saalau-Bethell S, Graham B. Protease inhibitors block multiple functions of the ns3/4a protease-helicase during the hepatitis c virus life cycle. J Virol 2015; 89(10): 5362-70.
[] [PMID: 25740995]
Meeprasert A, Hannongbua S, Rungrotmongkol T. Key binding and susceptibility of NS3/4A serine protease inhibitors against hepatitis C virus. J Chem Inf Model 2014; 54(4): 1208-17.
[] [PMID: 24689657]
Espinosa M, Hernàndez J, Arenas MD, Carnicer F, Caramelo C, Fabrizi F. Pegylated interferon (alone or with ribavirin) for chronic hepatitis C in haemodialysis population. Kidney Blood Press Res 2015; 40(3): 258-65.
[] [PMID: 25997572]
Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet 2011; 378(9785): 73-85.
[] [PMID: 21511329]
Wei L, Lim SG, Xie Q, et al. Sofosbuvir-velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial. Lancet Gastroenterol Hepatol 2019; 4(2): 127-34.
[] [PMID: 30555048]
Heo YA, Deeks ED. Sofosbuvir/Velpatasvir/Voxilaprevir: A Review in Chronic Hepatitis C. Drugs 2018; 78(5): 577-87.
[] [PMID: 29546556]
Taylor JG, Zipfel S, Ramey K, et al. Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857): A component of Vosevi®. Bioorg Med Chem Lett 2019; 29(16): 2428-36.
[] [PMID: 31133531]
de Leuw P, Stephan C. Protease inhibitors for the treatment of hepatitis C virus infection. GMS Infect Dis 2017; 5: Doc08.
[PMID: 30671330]
Xue W, Ban Y, Liu H, Yao X. Computational study on the drug resistance mechanism against HCV NS3/4A protease inhibitors vaniprevir and MK-5172 by the combination use of molecular dynamics simulation, residue interaction network, and substrate envelope analysis. J Chem Inf Model 2014; 54(2): 621-33.
[] [PMID: 23745769]
Romano KP, Ali A, Aydin C, et al. The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors. PLoS Pathog 2012; 8(7)e1002832
[] [PMID: 22910833]
Paixão ES, Teixeira MG, Rodrigues LC. Zika, chikungunya and dengue: the causes and threats of new and re-emerging arboviral diseases. BMJ Glob Health 2018; 3(Suppl. 1).e000530
[] [PMID: 29435366]
Boldescu V, Behnam MAM, Vasilakis N, Klein CD. Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond. Nat Rev Drug Discov 2017; 16(8): 565-86.
[] [PMID: 28473729]
Lim SP, Wang QY, Noble CG, et al. Ten years of dengue drug discovery: progress and prospects. Antiviral Res 2013; 100(2): 500-19.
[] [PMID: 24076358]
Kok WM. New developments in flavivirus drug discovery. Expert Opin Drug Discov 2016; 11(5): 433-45.
[] [PMID: 26966889]
Hasan SS, Sevvana M, Kuhn RJ, Rossmann MG. Structural biology of Zika virus and other flaviviruses. Nat Struct Mol Biol 2018; 25(1): 13-20.
[] [PMID: 29323278]
Kaptein SJ, Neyts J. Towards antiviral therapies for treating dengue virus infections. Curr Opin Pharmacol 2016; 30: 1-7.
[] [PMID: 27367615]
Kalayanarooj S. Clinical Manifestations and Management of Dengue/DHF/DSS. Trop Med Health 2011; 39(4)(Suppl.): 83-7.
[] [PMID: 22500140]
White JP, Xiong S, Malvin NP, Khoury-Hanold W, Heuckeroth RO, Stappenbeck TS, et al. Intestinal dysmotility syndromes following systemic infection by flaviviruses. Cell 2018; 175(5): 1198-212. e12
Skoreński M MA, Pyrć K, Sieńczyk M, Oleksyszyn J. Inhibitors compounds of the flavivirus replication process 2017; 14(1): 95.
García LL, Padilla L, Castaño JC. Inhibitors compounds of the flavivirus replication process. Virol J 2017; 14(1): 95.
[] [PMID: 28506240]
Hercík K, Kozak J, Šála M, et al. Adenosine triphosphate analogs can efficiently inhibit the Zika virus RNA-dependent RNA polymerase. Antiviral Res 2017; 137: 131-3.
[] [PMID: 27902932]
Nitsche C. Strategies towards protease inhibitors for emerging flaviviruses. Adv Exp Med Biol 2018; 1062: 175-86.
[] [PMID: 29845533]
Dubankova A, Boura E. Structure of the yellow fever NS5 protein reveals conserved drug targets shared among flaviviruses. Antiviral Res 2019. 169104536
[] [PMID: 31202975]
Hernandez J, Hoffer L, Coutard B, et al. Optimization of a fragment linking hit toward Dengue and Zika virus NS5 methyltransferases inhibitors. Eur J Med Chem 2019; 161: 323-33.
[] [PMID: 30368131]
Hercik K, Brynda J, Nencka R, Boura E. Structural basis of Zika virus methyltransferase inhibition by sinefungin. Arch Virol 2017; 162(7): 2091-6.
[] [PMID: 28357511]
Coutard B, Barral K, Lichière J, et al. Zika virus methyltransferase: structure and functions for drug design perspectives. J Virol 2017; 91(5): e02202-16.
[] [PMID: 28031359]
Brecher M, Chen H, Li Z, et al. Identification and characterization of novel broad-spectrum inhibitors of the flavivirus methyltransferase. ACS Infect Dis 2015; 1(8): 340-9.
[] [PMID: 26726314]
Kaaijk P, Luytjes W. Are we prepared for emerging flaviviruses in Europe? Challenges for vaccination. Hum Vaccin Immunother 2018; 14(2): 337-44.
[] [PMID: 29053401]
Rey FA, Stiasny K, Vaney MC, Dellarole M, Heinz FX. The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design. EMBO Rep 2018; 19(2): 206-24.
[] [PMID: 29282215]
Poland GA, Kennedy RB, Ovsyannikova IG, Palacios R, Ho PL, Kalil J. Development of vaccines against Zika virus. Lancet Infect Dis 2018; 18(7): e211-9.
[] [PMID: 29396004]
Garmaroudi FS, Marchant D, Hendry R, et al. Coxsackievirus B3 replication and pathogenesis. Future Microbiol 2015; 10(4): 629-53.
[] [PMID: 25865198]
Alidjinou EK, Sané F, Bertin A, Caloone D, Hober D. Persistent infection of human pancreatic cells with Coxsackievirus B4 is cured by fluoxetine. Antiviral Res 2015; 116: 51-4.
[] [PMID: 25655448]
Sin J, Mangale V, Thienphrapa W, Gottlieb RA, Feuer R. Recent progress in understanding coxsackievirus replication, dissemination, and pathogenesis. Virology 2015; 484: 288-304.
[] [PMID: 26142496]
Gruez A, Selisko B, Roberts M, et al. The crystal structure of coxsackievirus B3 RNA-dependent RNA polymerase in complex with its protein primer VPg confirms the existence of a second VPg binding site on Picornaviridae polymerases. J Virol 2008; 82(19): 9577-90.
[] [PMID: 18632861]
Gong P, Kortus MG, Nix JC, Davis RE, Peersen OB. Structures of coxsackievirus, rhinovirus, and poliovirus polymerase elongation complexes solved by engineering RNA mediated crystal contacts. PLoS One 2013; 8(5)e60272
[] [PMID: 23667424]
Garmaroudi FS, Marchant D, Hendry R, et al. Coxsackievirus B3 replication and pathogenesis. Future Microbiol 2015; 10(4): 629-53.
[] [PMID: 25865198]
Campagnola G, Weygandt M, Scoggin K, Peersen O. Crystal structure of coxsackievirus B3 3Dpol highlights the functional importance of residue 5 in picornavirus polymerases. J Virol 2008; 82(19): 9458-64.
[] [PMID: 18632862]
Karr JP, Peersen OB. ATP is an allosteric inhibitor of coxsackievirus b3 polymerase. Biochemistry 2016; 55(28): 3995-4002.
[] [PMID: 27319576]
Ulferts R, de Boer SM, van der Linden L, et al. Screening of a library of fda-approved drugs identifies several enterovirus replication inhibitors that target viral protein 2c. Antimicrob Agents Chemother 2016; 60(5): 2627-38.
[] [PMID: 26856848]
Lambert N, Strebel P, Orenstein W, Icenogle J, Poland GA. Rubella. Lancet 2015; 385(9984): 2297-307.
[] [PMID: 25576992]
Mejdrová I, Chalupská D, Plačková P, et al. Rational design of novel highly potent and selective phosphatidylinositol 4-kinase iiiβ (pi4kb) inhibitors as broad-spectrum antiviral agents and tools for chemical biology. J Med Chem 2017; 60(1): 100-18.
[] [PMID: 28004945]
Mejdrová I, Chalupská D, Kögler M, et al. Highly selective phosphatidylinositol 4-kinase iiiβ inhibitors and structural insight into their mode of action. J Med Chem 2015; 58(9): 3767-93.
[] [PMID: 25897704]
Tyor W, Harrison T. Mumps and rubella. Handb Clin Neurol 2014; 123: 591-600.
[] [PMID: 25015506]
Fontana J, Tzeng WP, Calderita G, Fraile-Ramos A, Frey TK, Risco C. Novel replication complex architecture in rubella replicon-transfected cells. Cell Microbiol 2007; 9(4): 875-90.
[] [PMID: 17087733]
Dubé M, Rey FA, Kielian M. Rubella virus: first calcium-requiring viral fusion protein. PLoS Pathog 2014; 10(12)e1004530
[] [PMID: 25474548]
Mangala Prasad V, Willows SD, Fokine A, et al. Rubella virus capsid protein structure and its role in virus assembly and infection. Proc Natl Acad Sci USA 2013; 110(50): 20105-10.
[] [PMID: 24282305]
Mangala Prasad V, Klose T, Rossmann MG. Assembly, maturation and three-dimensional helical structure of the teratogenic rubella virus. PLoS Pathog 2017; 13(6)e1006377
[] [PMID: 28575072]
Kowalzik F, Faber J, Knuf M. MMR and MMRV vaccines. Vaccine 2018; 36(36): 5402-7.
[] [PMID: 28757060]
Hviid A, Hansen JV, Frisch M, Melbye M. Measles, mumps, rubella vaccination and autism: A nationwide cohort study 2019.
Petrova EK, Dmitrieva AA, Trifonova EA, Nikitin NA, Karpova OV. The key role of rubella virus glycoproteins in the formation of immune response, and perspectives on their use in the development of new recombinant vaccines. Vaccine 2016; 34(8): 1006-11.
[] [PMID: 26776468]
Hashiguchi T, Fukuda Y, Matsuoka R, et al. Structures of the prefusion form of measles virus fusion protein in complex with inhibitors. Proc Natl Acad Sci USA 2018; 115(10): 2496-501.
[] [PMID: 29463726]
Moss WJ, Griffin DE. Global measles elimination. Nat Rev Microbiol 2006; 4(12): 900-8.
[] [PMID: 17088933]
Duke T, Mgone CS. Measles: not just another viral exanthem. Lancet 2003; 361(9359): 763-73.
[] [PMID: 12620751]
Ndungu JM, Krumm SA, Yan D, et al. Non-nucleoside inhibitors of the measles virus RNA-dependent RNA polymerase: synthesis, structure-activity relationships, and pharmacokinetics. J Med Chem 2012; 55(9): 4220-30.
[] [PMID: 22480182]
Rota PA, Moss WJ, Takeda M, de Swart RL, Thompson KM, Goodson JL. Measles. Nat Rev Dis Primers 2016; 2: 16049.
[] [PMID: 27411684]
Moss WJ, Griffin DE. Global measles elimination. Nat Rev Microbiol 2006; 4(12): 900-8.
[] [PMID: 17088933]
Griffin DE, Lin WH, Pan CH. Measles virus, immune control, and persistence. FEMS Microbiol Rev 2012; 36(3): 649-62.
[] [PMID: 22316382]
Plemper RK, Snyder JP. Measles control--can measles virus inhibitors make a difference? Curr Opin Investig Drugs 2009; 10(8): 811-20.
[PMID: 19649926]
Ohimain EI. Recent advances in the development of vaccines for Ebola virus disease. Virus Res 2016; 211: 174-85.
[] [PMID: 26596227]
McElroy AK, Erickson BR, Flietstra TD, et al. Ebola hemorrhagic Fever: novel biomarker correlates of clinical outcome. J Infect Dis 2014; 210(4): 558-66.
[] [PMID: 24526742]
Baseler L, Chertow DS, Johnson KM, Feldmann H, Morens DM. The pathogenesis of ebola virus disease. Annu Rev Pathol 2017; 12: 387-418.
[] [PMID: 27959626]
Leligdowicz A, Fischer WA II, Uyeki TM, et al. Ebola virus disease and critical illness. Crit Care 2016; 20(1): 217.
[] [PMID: 27468829]
Warren TK, Wells J, Panchal RG, et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature 2014; 508(7496): 402-5.
[] [PMID: 24590073]
Sissoko D, Laouenan C, Folkesson E, et al. Correction: Experimental treatment with favipiravir for ebola virus disease (the jiki trial): a historically controlled, single-arm proof-of-concept trial in guinea. PLoS Med 2016; 13(4)e1002009
[] [PMID: 27046271]
Balmith M, Faya M, Soliman ME. Ebola virus: A gap in drug design and discovery - experimental and computational perspective. Chem Biol Drug Des 2017; 89(3): 297-308.
[] [PMID: 27637475]
Xu W, Luthra P, Wu C, et al. Ebola virus VP30 and nucleoprotein interactions modulate viral RNA synthesis. Nat Commun 2017; 8: 15576.
[] [PMID: 28593988]
Malvy D, McElroy AK, de Clerck H, Günther S, van Griensven J. Ebola virus disease. Lancet 2019; 393(10174): 936-48.
[] [PMID: 30777297]
Borchers AT, Chang C, Gershwin ME, Gershwin LJ. Respiratory syncytial virus--a comprehensive review. Clin Rev Allergy Immunol 2013; 45(3): 331-79.
[] [PMID: 23575961]
Griffiths C, Drews SJ, Marchant DJ. Respiratory syncytial virus: infection, detection, and new options for prevention and treatment. Clin Microbiol Rev 2017; 30(1): 277-319.
[] [PMID: 27903593]
Xing Y, Proesmans M. New therapies for acute RSV infections: where are we? Eur J Pediatr 2019; 178(2): 131-8.
[] [PMID: 30610420]
Battles MB, McLellan JS. Respiratory syncytial virus entry and how to block it. Nat Rev Microbiol 2019; 17(4): 233-45.
[] [PMID: 30723301]
Tahamtan A, Askari FS, Bont L, Salimi V. Disease severity in respiratory syncytial virus infection: Role of host genetic variation. Rev Med Virol 2019; 29(2)e2026
[] [PMID: 30609190]
Tawar RG, Duquerroy S, Vonrhein C, et al. Crystal structure of a nucleocapsid-like nucleoprotein-RNA complex of respiratory syncytial virus. Science 2009; 326(5957): 1279-83.
[] [PMID: 19965480]
Cox R, Plemper RK. Structure-guided design of small-molecule therapeutics against RSV disease. Expert Opin Drug Discov 2016; 11(6): 543-56.
[] [PMID: 27046051]
Ruigrok RW, Crépin T. Nucleoproteins of negative strand RNA viruses; RNA binding, oligomerisation and binding to polymerase co-factor. Viruses 2010; 2(1): 27-32.
[] [PMID: 21994598]
Mahadevia PJ, Masaquel AS, Polak MJ, Weiner LB. Cost utility of palivizumab prophylaxis among pre-term infants in the United States: a national policy perspective. J Med Econ 2012; 15(5): 987-96.
[] [PMID: 22574798]
Gilani U, Shaukat M, Rasheed A, et al. The implication of CRISPR/Cas9 genome editing technology in combating human oncoviruses. J Med Virol 2019; 91(1): 1-13.
[] [PMID: 30133783]
Rey FA, Stiasny K, Vaney MC, Dellarole M, Heinz FX. The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design. EMBO Rep 2018; 19(2): 206-24.
[] [PMID: 29282215]
Martinez JP, Sasse F, Brönstrup M, Diez J, Meyerhans A. Antiviral drug discovery: broad-spectrum drugs from nature. Nat Prod Rep 2015; 32(1): 29-48.
[] [PMID: 25315648]
Šebera J, Dubankova A, Sychrovský V, Ruzek D, Boura E, Nencka R. The structural model of Zika virus RNA-dependent RNA polymerase in complex with RNA for rational design of novel nucleotide inhibitors. Sci Rep 2018; 8(1): 11132.
[] [PMID: 30042483]
Hassan AS, Bibby DF, Mwaringa SM, et al. Presence, persistence and effects of pre-treatment HIV-1 drug resistance variants detected using next generation sequencing: A Retrospective longitudinal study from rural coastal Kenya. PLoS One 2019; 14(2)e0210559
[] [PMID: 30759103]
Phillips AN, Venter F, Havlir D, et al. Risks and benefits of dolutegravir-based antiretroviral drug regimens in sub-Saharan Africa: a modelling study. Lancet HIV 2019; 6(2): e116-27.
[] [PMID: 30503325]
Bauer L, Lyoo H, van der Schaar HM, Strating JR, van Kuppeveld FJ. Direct-acting antivirals and host-targeting strategies to combat enterovirus infections. Curr Opin Virol 2017; 24: 1-8.
[] [PMID: 28411509]
Saiz JC, Oya NJ, Blázquez AB, Escribano-Romero E, Martín-Acebes MA. Host-directed antivirals: a realistic alternative to fight zika virus. Viruses 2018; 10(9)E453
[] [PMID: 30149598]
Shortridge MD, Wille PT, Jones AN, et al. An ultra-high affinity ligand of HIV-1 TAR reveals the RNA structure recognized by P-TEFb. Nucleic Acids Res 2019; 47(3): 1523-31.
[] [PMID: 30481318]
Quan X, Sun D, Zhou J. Molecular mechanism of HIV-1 TAT peptide and its conjugated gold nanoparticles translocating across lipid membranes. Phys Chem Chem Phys 2019; 21(20): 10300-10.
[] [PMID: 31070638]
Aguado LC, Jordan TX, Hsieh E, et al. Homologous recombination is an intrinsic defense against antiviral RNA interference. Proc Natl Acad Sci USA 2018; 115(39): E9211-9.
[] [PMID: 30209219]
Nguyen TH, Liu X, Su ZZ, Hsu AC, Foster PS, Yang M. Potential role of micrornas in the regulation of antiviral responses to influenza infection. Front Immunol 2018; 9: 1541.
[] [PMID: 30022983]
Yen PS, James A, Li JC, Chen CH, Failloux AB. Synthetic miRNAs induce dual arboviral-resistance phenotypes in the vector mosquito Aedes aegypti. Commun Biol 2018; 1: 11.
[] [PMID: 30271898]
Kloc A, Rai DK, Rieder E. The roles of picornavirus untranslated regions in infection and innate immunity. Front Microbiol 2018; 9: 485.
[] [PMID: 29616004]
Liao KC, Chuo V, Ng WC, et al. Identification and characterization of host proteins bound to dengue virus 3′ UTR reveal an antiviral role for quaking proteins. RNA 2018; 24(6): 803-14.
[] [PMID: 29572260]
Anasir MI, Poh CL. Structural vaccinology for viral vaccine design. Front Microbiol 2019; 10: 738.
[] [PMID: 31040832]
Shameer K, Johnson KW, Readhead B. Rapid therapeutic recommendations in the context of a global public health crisis using translational bioinformatics approaches: a proof-of-concept study using nipah virus infection. bioRxiv 2018. 333021
Zentner I, Sierra LJ, Fraser AK, et al. Identification of a small-molecule inhibitor of HIV-1 assembly that targets the phosphatidylinositol (4,5)-bisphosphate binding site of the HIV-1 matrix protein. ChemMedChem 2013; 8(3): 426-32.
[] [PMID: 23361947]
Thenin-Houssier S, de Vera IM, Pedro-Rosa L, et al. Ebselen, a small-molecule capsid inhibitor of hiv-1 replication. Antimicrob Agents Chemother 2016; 60(4): 2195-208.
[] [PMID: 26810656]
Balasubramaniam M, Zhou J, Addai A, et al. PF74 inhibits hiv-1 integration by altering the composition of the preintegration complex. J Virol 2019; 93(6): e01741-18.
[] [PMID: 30567984]
Thenin-Houssier S, Valente ST. HIV-1 Capsid Inhibitors as Antiretroviral Agents. Curr HIV Res 2016; 14(3): 270-82.
[] [PMID: 26957201]
Sancineto L, Mariotti A, Bagnoli L, et al. Design and Synthesis of DiselenoBisBenzamides (DISeBAs) as Nucleocapsid Protein 7 (NCp7) Inhibitors with anti-HIV Activity. J Med Chem 2015; 58(24): 9601-14.
[] [PMID: 26613134]
Rice WG, Turpin JA, Huang M, et al. Azodicarbonamide inhibits HIV-1 replication by targeting the nucleocapsid protein. Nat Med 1997; 3(3): 341-5.
[] [PMID: 9055865]
Collier AC, Coombs RW, Schoenfeld DA, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. N Engl J Med 1996; 334(16): 1011-7.
[] [PMID: 8598838]
Martinez-Cajas JL, Wainberg MA. Protease inhibitor resistance in HIV-infected patients: molecular and clinical perspectives. Antiviral Res 2007; 76(3): 203-21.
[] [PMID: 17673305]
Lv Z, Chu Y, Wang Y. HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV AIDS (Auckl) 2015; 7: 95-104.
[PMID: 25897264]
Atta MG, De Seigneux S, Lucas GM. Clinical Pharmacology in HIV Therapy. Clin J Am Soc Nephrol 2019; 14(3): 435-44.
[] [PMID: 29844056]
Yavuz B, Morgan JL, Showalte L, Horng KR, Dandekar S, Herrera C, et al. Pharmaceutical Approaches to HIV Treatment and Prevention. Adv Ther 2018. 11800054
De Clercq E. The history of antiretrovirals: key discoveries over the past 25 years. Rev Med Virol 2009; 19(5): 287-99.
[] [PMID: 19714702]
Pancera M, Lai YT, Bylund T, et al. Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529. Nat Chem Biol 2017; 13(10): 1115-22.
[] [PMID: 28825711]
Yi HA, Fochtman BC, Rizzo RC, Jacobs A. Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41. Curr HIV Res 2016; 14(3): 283-94.
[] [PMID: 26957202]
Lu L, Yu F, Cai L, Debnath AK, Jiang S. Development of small-molecule hiv entry inhibitors specifically targeting gp120 or gp41. Curr Top Med Chem 2016; 16(10): 1074-90.
[] [PMID: 26324044]
Kota S, Takahashi V, Ni F, Snyder JK, Strosberg AD. Direct binding of a hepatitis C virus inhibitor to the viral capsid protein. PLoS One 2012; 7(2)e32207
[] [PMID: 22389688]
Lee M, Yang J, Jo E, et al. A novel inhibitor idpp interferes with entry and egress of hcv by targeting glycoprotein e1 in a genotype-specific manner. Sci Rep 2017; 7: 44676.
[] [PMID: 28333153]
Al Olaby RR, Cocquerel L, Zemla A, et al. Identification of a novel drug lead that inhibits HCV infection and cell-to-cell transmission by targeting the HCV E2 glycoprotein. PLoS One 2014; 9(10)e111333
[] [PMID: 25357246]
Behmard E, Abdolmaleki P, Taghdir M. Understanding the inhibitory mechanism of BIT225 drug against p7 viroporin using computational study. Biophys Chem 2018; 233: 47-54.
[] [PMID: 29169687]
Shaw J, Fishwick CW, Harris M. Epoxide based inhibitors of the hepatitis C virus non-structural 2 autoprotease. Antiviral Res 2015; 117: 20-6.
[] [PMID: 25703928]
Jiang Y, Andrews SW, Condroski KR, et al. Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease. J Med Chem 2014; 57(5): 1753-69.
[] [PMID: 23672640]
Einav S, Sobol HD, Gehrig E, Glenn JS. The hepatitis C virus (HCV) NS4B RNA binding inhibitor clemizole is highly synergistic with HCV protease inhibitors. J Infect Dis 2010; 202(1): 65-74.
[] [PMID: 20486856]
Dufner-Beattie J, O’Guin A, O’Guin S, et al. Identification of AP80978, a novel small-molecule inhibitor of hepatitis C virus replication that targets NS4B. Antimicrob Agents Chemother 2014; 58(6): 3399-410.
[] [PMID: 24709254]
Phillips B, Cai R, Delaney W, et al. Highly potent HCV NS4B inhibitors with activity against multiple genotypes. J Med Chem 2014; 57(5): 2161-6.
[] [PMID: 24512292]
Li DK, Chung RT. Overview of direct-acting antiviral drugs and drug resistance of hepatitis c virus. Methods Mol Biol 2019; 1911: 3-32.
[] [PMID: 30593615]
Sheldon J, Barreiro P, Soriano V. Novel protease and polymerase inhibitors for the treatment of hepatitis C virus infection. Expert Opin Investig Drugs 2007; 16(8): 1171-81.
[] [PMID: 17685867]
Byrd CM, Dai D, Grosenbach DW, et al. A novel inhibitor of dengue virus replication that targets the capsid protein. Antimicrob Agents Chemother 2013; 57(1): 15-25.
[] [PMID: 23070172]
Rausch K, Hackett BA, Weinbren NL, et al. Screening Bioactives Reveals Nanchangmycin as a Broad Spectrum Antiviral Active against Zika Virus. Cell Rep 2017; 18(3): 804-15.
[] [PMID: 28099856]
de Wispelaere M, Lian W, Potisopon S, Li PC, Jang J, Ficarro SB. Inhibition of flaviviruses by targeting a conserved pocket on the viral envelope protein. Cell Chem Biol 2018; 25(8): 1006-6. e8
García LL, Padilla L, Castaño JC. Inhibitors compounds of the flavivirus replication process. Virol J 2017; 14(1): 95.
[] [PMID: 28506240]
Li Z, Brecher M, Deng YQ, et al. Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction. Cell Res 2017; 27(8): 1046-64.
[] [PMID: 28685770]
Shiryaev SA, Farhy C, Pinto A, et al. Characterization of the Zika virus two-component NS2B-NS3 protease and structure-assisted identification of allosteric small-molecule antagonists. Antiviral Res 2017; 143: 218-29.
[] [PMID: 28461069]
Albulescu IC, Kovacikova K, Tas A, Snijder EJ, van Hemert MJ. Suramin inhibits Zika virus replication by interfering with virus attachment and release of infectious particles. Antiviral Res 2017; 143: 230-6.
[] [PMID: 28461070]
Wang QY, Dong H, Zou B, et al. Discovery of Dengue Virus NS4B Inhibitors. J Virol 2015; 89(16): 8233-44.
[] [PMID: 26018165]
Xie X, Zou J, Wang QY, Shi PY. Targeting dengue virus NS4B protein for drug discovery. Antiviral Res 2015; 118: 39-45.
[] [PMID: 25796970]
Saiz JC, Martín-Acebes MA. The race to find antivirals for zika virus. Antimicrob Agents Chemother 2017; 61(6): e00411-7.
[] [PMID: 28348160]
Xu HT, Hassounah SA, Colby-Germinario SP, et al. Purification of Zika virus RNA-dependent RNA polymerase and its use to identify small-molecule Zika inhibitors. J Antimicrob Chemother 2017; 72(3): 727-34.
[] [PMID: 28069884]
Mottin M, Borba JVVB, Braga RC, et al. The A-Z of Zika drug discovery. Drug Discov Today 2018; 23(11): 1833-47.
[] [PMID: 29935345]
Zhao Y, Ren J, Harlos K, et al. Toremifene interacts with and destabilizes the Ebola virus glycoprotein. Nature 2016; 535(7610): 169-72.
[] [PMID: 27362232]
Ren J, Zhao Y, Fry EE, Stuart DI. target identification and mode of action of four chemically divergent drugs against ebolavirus infection. J Med Chem 2018; 61(3): 724-33.
[] [PMID: 29272110]
Basu A, Mills DM, Mitchell D, et al. Novel small molecule entry inhibitors of ebola virus. J Infect Dis 2015; 212(Suppl. 2): S425-34.
[] [PMID: 26206510]
Yuan S. Possible FDA-approved drugs to treat Ebola virus infection. Infect Dis Poverty 2015; 4: 23.
[] [PMID: 25984303]
Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res 2014; 105: 17-21.
[] [PMID: 24583123]
Challa S, Scott AD, Yuzhakov O, et al. Mechanism of action for respiratory syncytial virus inhibitor RSV604. Antimicrob Agents Chemother 2015; 59(2): 1080-7.
[] [PMID: 25451060]
DeVincenzo J, Cehelsky JE, Alvarez R, et al. Evaluation of the safety, tolerability and pharmacokinetics of ALN-RSV01, a novel RNAi antiviral therapeutic directed against respiratory syncytial virus (RSV). Antiviral Res 2008; 77(3): 225-31.
[] [PMID: 18242722]
Tripp RA, Power UF, Openshaw PJM, Kauvar LM. Respiratory Syncytial Virus: Targeting the G Protein Provides a New Approach for an Old Problem. J Virol 2018; 92(3): e01302-17.
[] [PMID: 29118126]
Heylen E, Neyts J, Jochmans D. Drug candidates and model systems in respiratory syncytial virus antiviral drug discovery. Biochem Pharmacol 2017; 127: 1-12.
[] [PMID: 27659812]
Xing Y, Proesmans M. New therapies for acute RSV infections: where are we? Eur J Pediatr 2019; 178(2): 131-8.
[] [PMID: 30610420]
Heylen E, Neyts J, Jochmans D. Drug candidates and model systems in respiratory syncytial virus antiviral drug discovery. Biochem Pharmacol 2017; 127: 1-12.
[] [PMID: 27659812]
Tang W, Li M, Liu Y, et al. Small molecule inhibits respiratory syncytial virus entry and infection by blocking the interaction of the viral fusion protein with the cell membrane. FASEB J 2019; 33(3): 4287-99.
[] [PMID: 30571312]
Noton SL, Nagendra K, Dunn EF, Mawhorter ME, Yu Q, Fearns R. Respiratory syncytial virus inhibitor az-27 differentially inhibits different polymerase activities at the promoter. J Virol 2015; 89(15): 7786-98.
[] [PMID: 25995255]
Fearns R, Deval J. New antiviral approaches for respiratory syncytial virus and other mononegaviruses: Inhibiting the RNA polymerase. Antiviral Res 2016; 134: 63-76.
[] [PMID: 27575793]
Lai SH, Stein DA, Guerrero-Plata A, et al. Inhibition of respiratory syncytial virus infections with morpholino oligomers in cell cultures and in mice. Mol Ther 2008; 16(6): 1120-8.
[] [PMID: 18443602]

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Year: 2020
Published on: 22 January, 2020
Page: [105 - 124]
Pages: 20
DOI: 10.2174/1389450119666190920153247
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