Generic placeholder image

Current Drug Targets


ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

Review Article (Mini-Review)

Potential Role of Endonuclease Inhibition and Other Targets in the Treatment of Influenza

Author(s): Doreen Szollosi* and Ashley Bill

Volume 21 , Issue 2 , 2020

Page: [202 - 211] Pages: 10

DOI: 10.2174/1389450120666190801115130

Price: $65


Background: Influenza is a single-stranded RNA virus that is highly contagious and infects millions of people in the U.S. annually. Due to complications, approximately 959,000 people were hospitalized and another 79,400 people died during the 2017-2018 flu season. While the best methods of prevention continue to be vaccination and hygiene, antiviral treatments may help reduce symptoms for those who are infected. Until recently, the only antiviral drugs in use have been the neuraminidase inhibitors: oseltamivir, zanamivir, and peramivir.

Objective: We reviewed novel drug targets that can be used in the treatment of influenza, particularly in the case of neuraminidase inhibitor-resistant strains that may emerge.

Results: More recently, a drug with a new mechanism of action has been approved. Baloxavir marboxil inhibits the influenza cap-dependent endonuclease that is needed for the virus to initiate replication within the host cell. This endonuclease target is within the polymerase acid (PA) subunit of RNA polymerase. Since the RNA-dependent RNA polymerase consists of two other subunits, polymerase basic 1 and 2, RNA polymerase has several targets that prevent viral replication. Other targets still under investigation include viral kinases, endocytosis, and viral fusion.

Conclusion: Due to the possibility of viral mutations and resistance, it is important to have antivirals with different mechanisms available, especially in the case of a new pandemic strain. Several novel antivirals are within various stages of development and may represent new classes of treatments that can reduce symptoms and complications in those patients who may be at higher risk.

Keywords: Influenza, hemagglutinin, neuraminidase, antivirals, resistance, endonuclease, polymerase, pandemic.

Graphical Abstract
Barnett R. Influenza Lancet 2019; 393(10170): 396.
[] [PMID: 30722953]
Biere B, Bauer B, Schweiger B. Differentiation of influenza B virus lineages Yamagata and Victoria by real-time PCR. J Clin Microbiol 2010; 48(4): 1425-7.
[] [PMID: 20107085]
Saunders-Hastings PR, Krewski D. Reviewing the history of pandemic influenza: understanding patterns of emergence and transmission. Pathogens 2016; 5(4): 66.
[] [PMID: 27929449]
Koonin LM, Patel A. Timely antiviral administration during an influenza pandemic: key components. Am J Public Health 2018; 108(S3)(Suppl. 3): S215-20.
[] [PMID: 30192657]
Ilyushina NA, Bovin NV, Webster RG, Govorkova EA. Combination chemotherapy, a potential strategy for reducing the emergence of drug-resistant influenza A variants. Antiviral Res 2006; 70(3): 121-31.
[] [PMID: 16516984]
Zheng W, Tao YJ. Structure and assembly of the influenza A virus ribonucleoprotein complex. FEBS Lett 2013; 587(8): 1206-14.
[] [PMID: 23499938]
Webby RJ, Webster RG. Are we ready for pandemic influenza? Science 2003; 302(5650): 1519-22.
[] [PMID: 14645836]
Stubbs TM, Te Velthuis AJW. The RNA-dependent RNA polymerase of the influenza A virus. Future Virol 2014; 9(9): 863-76.
[] [PMID: 25431616]
Kirkpatrick E, Qiu X, Wilson PC, Bahl J, Krammer F. The influenza head evolves faster than the stalk domain. Sci Rep 2018; 8: 10432.
[] [PMID: 29992986]
Pielak RM, Chou JJ. Influenza M2 proton channels. Biochim Biophys Acta 2011; 1808(2): 522-9.
[] [PMID: 20451491]
Engelhardt OG, Smith M, Fodor E. Association of the influenza A virus RNA-dependent RNA polymerase with cellular RNA polymerase II. J Virol 2005; 79(9): 5812-8.
[] [PMID: 15827195]
Omoto S, Speranzini V, Hashimoto T, et al. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep 2018; 8(1): 9633.
[] [PMID: 29941893]
O’Hanlon R, Shaw ML. Baloxavir marboxil: the new influenza drug on the market. Curr Opin Virol 2019; 35: 14-8.
[] [PMID: 30852344]
van de Wakker SI, Fischer MJE, Oosting RS. New drug-strategies to tackle viral-host interactions for the treatment of influenza virus infections. Eur J Pharmacol 2017; 809: 178-90.
[] [PMID: 28533172]
Leonov H, Astrahan P, Krugliak M, Arkin IT. How do aminoadamantanes block the influenza M2 channel, and how does resistance develop? J Am Chem Soc 2011; 133(25): 9903-11.
[] [PMID: 21534619]
Hussain M, Galvin HD, Haw TY, Nutsford AN, Husain M. Drug resistance in influenza A virus: the epidemiology and management. Infect Drug Resist 2017; 10: 121-34.
[] [PMID: 28458567]
Meindl P, Bodo G, Palese P, Schulman J, Tuppy H. Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. Virology 1974; 58(2): 457-63.
[] [PMID: 4362431]
Palese P, Compans RW. Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA): mechanism of action. J Gen Virol 1976; 33(1): 159-63.
[] [PMID: 978183]
Colman PM, Varghese JN, Laver WG. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 1983; 303(5912): 41-4.
[] [PMID: 6188957]
Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005; 353(13): 1363-73.
[] [PMID: 16192481]
Sheu TG, Deyde VM, Okomo-Adhiambo M, et al. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008. Antimicrob Agents Chemother 2008; 52(9): 3284-92.
[] [PMID: 18625765]
Hurt AC, Chotpitayasunondh T, Cox NJ, et al. Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives. Lancet Infect Dis 2012; 12(3): 240-8.
[] [PMID: 22186145]
Higgins RR, Beniprashad M, Chong-King E, et al. Recovery of influenza B virus with the H273Y point mutation in the neuraminidase active site from a human patient. J Clin Microbiol 2012; 50(7): 2500-2.
[] [PMID: 22535992]
Aoki FY, Macleod MD, Paggiaro P, et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother 2003; 51(1): 123-9.
[] [PMID: 12493796]
Gupta YK, Meenu M, Mohan P. The Tamiflu fiasco and lessons learnt. Indian J Pharmacol 2015; 47(1): 11-6.
[] [PMID: 25821304]
Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348: g2545.
[] [PMID: 24811411]
Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet 2015; 385(9979): 1729-37.
[] [PMID: 25640810]
WHO model list of essential medicines Adults, 20th edn (March 2017) Revised Aug 2017..
WHO model list of essential medicines for children 6th list (March 2017) Revised Aug 2017..
Eiland LS, Eiland EH. Zanamivir for the prevention of influenza in adults and children age 5 years and older. Ther Clin Risk Manag 2007; 3(3): 461-5.
[PMID: 18488077]
Murphy KR, Eivindson A, Pauksens K, et al. Efficacy and safety of inhaled zanamivir for the treatment of influenza in patients with asthma or chronic obstructive pulmonary disease: a double-blind, randomised, placebo-controlled, multicentre study. Clin Drug Investig 2000; 20: 337-49.
Noshi T, Kitano M, Taniguchi K, et al. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res 2018; 160: 109-17.
[] [PMID: 30316915]
Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med 2018; 379(10): 913-23.
[] [PMID: 30184455]
Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet 2000; 355(9218): 1845-50.
[] [PMID: 10866439]
Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA 2000; 283(8): 1016-24.
[] [PMID: 10697061]
Min J-Y, Subbarao K. Cellular targets for influenza drugs. Nat Biotechnol 2010; 28(3): 239-40.
[] [PMID: 20212486]
Pflug A, Gaudon S, Resa-Infante P, et al. Capped RNA primer binding to influenza polymerase and implications for the mechanism of cap-binding inhibitors. Nucleic Acids Res 2018; 46(2): 956-71.
[] [PMID: 29202182]
Clark MP, Ledeboer MW, Davies I, et al. Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2. J Med Chem 2014; 57(15): 6668-78.
[] [PMID: 25019388]
Trevejo JM, Asmal M, Vingerhoets J, et al. Pimodivir treatment in adult volunteers experimentally inoculated with live influenza virus: a Phase IIa, randomized, double-blind, placebo-controlled study. Antivir Ther 2017.
[] [PMID: 29244026]
Finberg RW, Lanno R, Anderson D, et al. Phase 2b study of pimodivir (JNJ-63623872) as monotherapy or in combination with oseltamivir for treatment of acute uncomplicated seasonal influenza A: TOPAZ trial. J Infect Dis 2019; 219(7): 1026-34.
[] [PMID: 30428049]
O’Neil B, Ison M, Hallouin-Bernard M, et al. The Opal Trial: a placebo-controlled phase 2b trial studying pimodivir plus oseltamivir vs placebo plus oseltamivir in adult and elderly hospitalized patients with influenza. A infection 2017September 10–13; Riga, Latvia 2017. Presented as a late-breaking abstract at the 6th ESWI Conference.
Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad, Ser B, Phys Biol Sci 2017; 93(7): 449-63.
[] [PMID: 28769016]
Furuta Y, Takahashi K, Fukuda Y, et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother 2002; 46(4): 977-81.
[] [PMID: 11897578]
Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res 2013; 100(2): 446-54.
[] [PMID: 24084488]
Kiso M, Takahashi K, Sakai-Tagawa Y, et al. T-705 (favipiravir) activity against lethal H5N1 influenza A viruses. Proc Natl Acad Sci USA 2010; 107(2): 882-7.
[] [PMID: 20080770]
Nagata T, Lefor AK, Hasegawa M, Ishii M. Favipiravir: a new medication for the Ebola virus disease pandemic. Disaster Med Public Health Prep 2015; 9(1): 79-81.
[] [PMID: 25544306]
Koszalka P, Tilmanis D, Hurt AC. Influenza antivirals currently in late-phase clinical trial. Influenza Other Respir Viruses 2017; 11(3): 240-6.
[] [PMID: 28146320]
Korba BE, Montero AB, Farrar K, et al. Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication. Antiviral Res 2008; 77(1): 56-63.
[] [PMID: 17888524]
Rossignol J-F. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res 2014; 110: 94-103.
[] [PMID: 25108173]
Haffizulla J, Hartman A, Hoppers M, et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis 2014; 14(7): 609-18.
[] [PMID: 24852376]
Malakhov MP, Aschenbrenner LM, Smee DF, et al. Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection. Antimicrob Agents Chemother 2006; 50(4): 1470-9.
[] [PMID: 16569867]
Moss RB, Hansen C, Sanders RL, Hawley S, Li T, Steigbigel RT. A phase II study of DAS181, a novel host directed antiviral for the treatment of influenza infection. J Infect Dis 2012; 206(12): 1844-51.
[] [PMID: 23045618]
Zitouni S, Nabais C, Jana SC, Guerrero A, Bettencourt-Dias M. Polo-like kinases: structural variations lead to multiple functions. Nat Rev Mol Cell Biol 2014; 15(7): 433-52.
[] [PMID: 24954208]
Kurokawa M, Koyama AH, Yasuoka S, Adachi A. Influenza virus overcomes apoptosis by rapid multiplication. Int J Mol Med 1999; 3(5): 527-30.
[] [PMID: 10202186]
Diab A, Foca A, Fusil F, et al. Polo-like-kinase 1 is a proviral host factor for hepatitis B virus replication. Hepatology 2017; 66(6): 1750-65.
[] [PMID: 28445592]
Chen YC, Su WC, Huang JY, et al. Polo-like kinase 1 is involved in hepatitis C virus replication by hyperphosphorylating NS5A. J Virol 2010; 84(16): 7983-93.
[] [PMID: 20534861]
Pohl MO, von Recum-Knepper J, Rodriguez-Frandsen A, et al. Identification of Polo-like kinases as potential novel drug targets for influenza A virus. Sci Rep 2017; 7(1): 8629.
[] [PMID: 28819179]
Corti D, Voss J, Gamblin SJ, et al. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 2011; 333(6044): 850-6.
[] [PMID: 21798894]
Ekiert DC, Friesen RH, Bhabha G, et al. A highly conserved neutralizing epitope on group 2 influenza A viruses. Science 2011; 333(6044): 843-50.
[] [PMID: 21737702]
Tharakaraman K, Subramanian V, Cain D, Sasisekharan V, Sasisekharan R. Broadly neutralizing influenza hemagglutinin stem-specific antibody CR8020 targets residues that are prone to escape due to host selection pressure. Cell Host Microbe 2014; 15(5): 644-51.
[] [PMID: 24832457]
Gupta P, Kamath AV, Park S, et al. Preclinical pharmacokinetics of MHAA4549A, a human monoclonal antibody to influenza A virus, and the prediction of its efficacious clinical dose for the treatment of patients hospitalized with influenza A. MAbs 2016; 8(5): 991-7.
[] [PMID: 27031797]
Kallewaard NL, Corti D, Collins PJ, et al. Structure and function analysis of an antibody recognizing all influenza A subtypes. Cell 2016; 166(3): 596-608.
[] [PMID: 27453466]
McBride JM, Lim JJ, Burgess T, Deng R, Derby MA, Maia M, et al. Removal of Pb (II) ions by raw corn silk (Zea mays L.) as a novel biosorbent. Journal of the Taiwan Institute of Chemical Engineers 20171
Ali SO, Takas T, Nyborg A, et al. Evaluation of MEDI8852, an anti-influenza A monoclonal antibody, in treating acute uncomplicated influenza. Antimicrob Agents Chemother 2018; 62(11): e00694-18.
[] [PMID: 30150460]
Tharakaraman K, Subramanian V, Viswanathan K, et al. A broadly neutralizing human monoclonal antibody is effective against H7N9. Proc Natl Acad Sci USA 2015; 112(35): 10890-5.
[] [PMID: 26283346]
Baranovich T, Jones JC, Russier M, et al. The hemagglutinin stem-binding monoclonal antibody VIS410 controls influenza virus-induced acute respiratory distress syndrome. Antimicrob Agents Chemother 2016; 60(4): 2118-31.
[] [PMID: 26787699]
Wollacott AM, Boni MF, Szretter KJ, et al. Safety and upper respiratory pharmacokinetics of the hemagglutinin stalk-binding antibody VIS410 support treatment and prophylaxis based on population modeling of seasonal influenza A outbreaks. EBioMedicine 2016; 5: 147-55.
[] [PMID: 27077121]
Hershberger E, Sloan S, Narayan K, et al. Safety and efficacy of monoclonal antibody VIS410 in adults with uncomplicated influenza A infection: Results from a randomized, double-blind, phase-2, placebo-controlled study. EBioMedicine 2019; 40: 574-82.
[] [PMID: 30638863]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy