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Current medicinal chemistry
2018;25 (38): 5115-5127.

Influenza Virus: Small Molecule Therapeutics and Mechanisms of Antiviral Resistance.

Julianna Han, Jasmine Perez, Adam Schafer, Han Cheng, Norton Peet, Lijun Rong, Balaji Manicassamy
Author Information
  1. Julianna Han: Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, United States.
  2. Jasmine Perez: Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, United States.
  3. Adam Schafer: Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
  4. Han Cheng: Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
  5. Norton Peet: Chicago Biosolutions Inc. Chicago, United States.
  6. Lijun Rong: Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
  7. Balaji Manicassamy: Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, United States.
PMID: 28933281 DOI: 10.2174/0929867324666170920165926

Abstract

BACKGROUND: Influenza viruses cause severe upper respiratory illness in children and the elderly during seasonal epidemics. Influenza viruses from zoonotic reservoirs can also cause pandemics with significant loss of life in all age groups. Although vaccination is one of the most effective methods to protect against seasonal epidemics, seasonal vaccines vary in efficacy, can be ineffective in the elderly population, and do not provide protection against novel strains. Small molecule therapeutics are a critical part of our antiviral strategies to control influenza virus epidemics and pandemics as well as to ameliorate disease in elderly and immunocompromised individuals.
OBJECTIVE: This review aims to summarize the existing antiviral strategies for combating influenza viruses, the mechanisms of antiviral resistance for available drugs, and novel therapeutics currently in development.
METHODS: We systematically evaluated and synthesized the published scientific literature for mechanistic detail into therapeutic strategies against influenza viruses.
RESULTS: Current IAV strains have developed resistance to neuraminidase inhibitors and nearly complete resistance to M2 ion channel inhibitors, exacerbated by sub-therapeutic dosing used for treatment and chemoprophylaxis. New tactics include novel therapeutics targeting host components and combination therapy, which show potential for fighting influenza virus disease while minimizing viral resistance.
CONCLUSION: Antiviral drugs are crucial for controlling influenza virus disease burden, but their efficacy is limited by human misuse and the capacity of influenza viruses to circumvent antiviral barriers. To relieve the public health hardship of influenza virus, emerging therapies must be selected for their capacity to impede not only influenza virus disease, but also the development of antiviral resistance.

Keywords

Influenza virus anti-influenza drugs antiviral drugs antiviral resistance small molecule therapeutics.

References

Clin Microbiol Infect. 2015 Mar;21(3):222-5 [PMID: 25703253]
Antiviral Res. 2007 May;74(2):159-62 [PMID: 17137644]
J Biol Chem. 2009 Oct 23;284(43):29798-808 [PMID: 19638339]
N Engl J Med. 2005 Dec 22;353(25):2633-6 [PMID: 16371626]
J Infect Dis. 2010 Mar;201(5):740-5 [PMID: 20100088]
Antiviral Res. 2009 Feb;81(2):132-40 [PMID: 19028526]
J Virol. 2009 Oct;83(20):10366-73 [PMID: 19641000]
J Virol. 2016 May 27;90(12):5636-5642 [PMID: 27030270]
Lancet Infect Dis. 2014 Dec;14(12):1259-70 [PMID: 25213733]
PLoS Pathog. 2013 Feb;9(2):e1003176 [PMID: 23408893]
Emerg Infect Dis. 2013;19(9):1521-4 [PMID: 23965618]
Influenza Other Respir Viruses. 2013 Jan;7 Suppl 1:25-36 [PMID: 23279894]
Curr Opin Pharmacol. 2016 Oct;30:106-115 [PMID: 27570127]
Antimicrob Agents Chemother. 2015 May;59(5):2607-17 [PMID: 25691635]
Curr Opin Virol. 2014 Oct;8:22-9 [PMID: 24866471]
Influenza Other Respir Viruses. 2013 Jan;7 Suppl 1:37-43 [PMID: 23279895]
J Biol Chem. 2008 Jun 6;283(23):15921-31 [PMID: 18408016]
N Engl J Med. 2010 Sep 30;363(14):1381-2 [PMID: 20879894]
Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14216-21 [PMID: 21825125]
JAMA. 2006 Feb 22;295(8):891-4 [PMID: 16456087]
Clin Infect Dis. 1992 Aug;15(2):362-7; discussion 368-9 [PMID: 1520770]
J Virol. 2013 Oct;87(19):10524-38 [PMID: 23824822]
Antimicrob Agents Chemother. 2006 Apr;50(4):1470-9 [PMID: 16569867]
J Am Chem Soc. 2011 Jun 29;133(25):9903-11 [PMID: 21534619]
J Virol. 2010 Jun;84(11):5605-14 [PMID: 20237084]
Nat Commun. 2014 Sep 03;5:4794 [PMID: 25183443]
J Biol Chem. 2006 Apr 7;281(14):8997-9000 [PMID: 16407184]
Sci Rep. 2016 Feb 26;6:21662 [PMID: 26916998]
N Engl J Med. 2005 Dec 22;353(25):2667-72 [PMID: 16371632]
N Engl J Med. 2009 Dec 3;361(23):2296-7 [PMID: 19907034]
Cell Host Microbe. 2014 Dec 10;16(6):795-805 [PMID: 25464832]
Curr Opin Virol. 2016 Jun;18:126-34 [PMID: 27344481]
Antiviral Res. 2015 May;117:27-38 [PMID: 25721488]
Nature. 1993 Jun 3;363(6428):418-23 [PMID: 8502295]
Antimicrob Agents Chemother. 2009 Sep;53(9):3935-41 [PMID: 19596886]
Curr Top Microbiol Immunol. 1992;176:119-30 [PMID: 1600749]
Influenza Other Respir Viruses. 2017 May;11(3):240-246 [PMID: 28146320]
Nat Commun. 2014 Oct 09;5:5029 [PMID: 25297528]
J Infect Dis. 2010 Oct 15;202(8):1154-60 [PMID: 20831384]
Ann N Y Acad Sci. 1965 Jul 30;130(1):432-9 [PMID: 4285587]
EMBO J. 1985 Nov;4(11):3021-4 [PMID: 4065098]
Infect Ecol Epidemiol. 2011;1: [PMID: 22957113]
Antimicrob Agents Chemother. 2013 May;57(5):2231-42 [PMID: 23459490]
Rev Sci Tech. 2009 Apr;28(1):187-202 [PMID: 19618626]
Clin Infect Dis. 2010 Nov 15;51(10):1167-75 [PMID: 20936975]
J Virol. 2014 Feb;88(3):1447-60 [PMID: 24198411]
Science. 2010 Jun 4;328(5983):1272-5 [PMID: 20522774]
Antiviral Res. 2016 May;129:21-38 [PMID: 26872862]
Nat Rev Microbiol. 2014 Dec;12(12):822-31 [PMID: 25383601]
Lancet. 2005 Oct 1;366(9492):1175-81 [PMID: 16198766]
Lancet Infect Dis. 2014 Jul;14(7):609-18 [PMID: 24852376]
Adv Virol. 2013;2013:121924 [PMID: 23365574]
Clin Infect Dis. 2010 Oct 15;51(8):983-4 [PMID: 20858074]
Antiviral Res. 2015 May;117:10-9 [PMID: 25701593]
PLoS One. 2011;6(12):e29120 [PMID: 22195002]
Structure. 2011 Nov 9;19(11):1655-63 [PMID: 22078564]
MMWR Morb Mortal Wkly Rep. 2009 Sep 11;58(35):969-72 [PMID: 19745803]
Antiviral Res. 2013 Nov;100(2):446-54 [PMID: 24084488]
Infect Genet Evol. 2009 Mar;9(2):169-78 [PMID: 19022400]
J Infect Dis. 2012 Jul 15;206(2):148-57 [PMID: 22561367]
Antiviral Res. 2002 Aug;55(2):307-17 [PMID: 12103431]
Antiviral Res. 2011 Oct;92(1):27-36 [PMID: 21802447]
JAMA. 2009 Mar 11;301(10):1034-41 [PMID: 19255110]
J Am Chem Soc. 1997 Jan 29;119(4):681-90 [PMID: 16526129]
Emerg Infect Dis. 2009 Feb;15(2):155-62 [PMID: 19193257]
J Med Chem. 2000 Sep 21;43(19):3482-6 [PMID: 11000002]
Antiviral Res. 2016 Aug;132:170-7 [PMID: 27321665]
Viruses. 2015 Sep 14;7(9):4929-44 [PMID: 26389935]
Nat Rev Drug Discov. 2015 Mar;14(3):167-82 [PMID: 25722244]
Proteins. 2004 May 1;55(2):251-7 [PMID: 15048819]
J Antimicrob Chemother. 2016 Nov;71(11):3036-3045 [PMID: 27432605]
J Virol. 2013 Apr;87(8):4694-703 [PMID: 23408618]
J Infect Dis. 2009 May 15;199(10):1435-41 [PMID: 19392620]
Antiviral Res. 2015 Nov;123:114-9 [PMID: 26391974]
Cell Mol Life Sci. 2014 Oct;71(19):3659-83 [PMID: 24699705]
J Infect Dis. 2007 Jul 15;196(2):249-57 [PMID: 17570112]
Bioorg Med Chem Lett. 2011 Aug 15;21(16):4860-4 [PMID: 21741839]
PLoS One. 2012;7(1):e31006 [PMID: 22292088]
Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3669-74 [PMID: 26976575]
Antimicrob Agents Chemother. 1994 Dec;38(12):2827-37 [PMID: 7695269]
MMWR Recomm Rep. 2011 Jan 21;60(1):1-24 [PMID: 21248682]
J Virol. 1988 May;62(5):1508-12 [PMID: 3282079]
Antimicrob Agents Chemother. 2015 Mar;59(3):1569-82 [PMID: 25547360]
J Infect Dis. 1991 Nov;164(5):969-72 [PMID: 1940477]
Antiviral Res. 2014 Oct;110:94-103 [PMID: 25108173]
J Med Chem. 2014 Aug 14;57(15):6668-78 [PMID: 25019388]
Lancet. 2013 Jun 29;381(9885):2273-9 [PMID: 23726392]
Antimicrob Agents Chemother. 2010 May;54(5):1834-41 [PMID: 20194700]
Curr Opin Virol. 2015 Oct;14:71-8 [PMID: 26364134]
PLoS One. 2009 Nov 06;4(11):e7788 [PMID: 19893747]
Clin Infect Dis. 2009 Feb 15;48(4):389-96 [PMID: 19133796]
Antimicrob Agents Chemother. 2009 Jan;53(1):186-92 [PMID: 18955520]
J Virol. 1993 Sep;67(9):5585-94 [PMID: 7688826]
Euro Surveill. 2011 Jan 20;16(3): [PMID: 21262183]
PLoS One. 2014 Jul 03;9(7):e101325 [PMID: 24992479]
Nature. 2005 Oct 20;437(7062):1108 [PMID: 16228009]
Euro Surveill. 2015;20(45): [PMID: 26608955]
PLoS Pathog. 2014 Apr 03;10(4):e1004065 [PMID: 24699865]
Lancet. 2004 Aug 28-Sep 3;364(9436):759-65 [PMID: 15337401]
Emerg Infect Dis. 2010 Mar;16(3):493-6 [PMID: 20202427]
PLoS Med. 2010 Nov 02;7(11):e1000362 [PMID: 21072246]
Biochem Biophys Res Commun. 2009 Jul 31;385(3):390-4 [PMID: 19463784]
Antiviral Res. 2016 Aug;132:178-85 [PMID: 27265623]
J Infect Dis. 1989 Mar;159(3):430-5 [PMID: 2915166]
Trends Microbiol. 2014 Apr;22(4):183-91 [PMID: 24582528]

Grants

  1. R01 AI123359/NIAID NIH HHS
  2. R21 AI119297/NIAID NIH HHS
  3. T32 GM007183/NIGMS NIH HHS

MeSH Term

Animals
Antiviral Agents
Child
Drug Resistance, Viral
Enzyme Inhibitors
Humans
Influenza, Human
Orthomyxoviridae
Viral Proteins

Chemicals

Antiviral Agents
Enzyme Inhibitors
Viral Proteins
Journal Article Review

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