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Expert Opinion on Therapeutic Patents Volume 14, 2004 - Issue 8
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Review

Recent advances in the discovery and development of anti-influenza drugs

Klaus Klumpp Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. [email protected]
Pages 1153-1168 | Published online: 25 Feb 2005

Bibliography

  • COX NJ, SUBBARAO K: Global epidemiology of influenza: past and present. Ann. Rev Med. (2000) 51:407–421.
  • •Discussion of recent paradigm changes in influenza epidemiology.
  • SULLIVAN KM: Health impact of influenza in the United States. Pharmacoeconomics (1996) 9:26–33.
  • SKOWRONSKI D, KING A, TAM T et al.: Update: influenza activity - United States, 2003-04 Season. MMWR (2004) 53:284–287.
  • BRIDGES CB, HARPER SA, FUKUDA K, UYEKI TM, COX NJ, SINGLETON JA: Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR (2003) 52 (RR08) :1–36.
  • •Risk—benefit analysis of treatment and prophylaxis options.
  • SIMONSEN L, FUKUDA K, SCHONBERGER LB, COX NJ: The impact of influenza epidemics on hospitalizations. J . Infect. Dis. (2000) 181:831–837.
  • SHUI I, BHAT N, GLOVER M, POSEY D: Update: influenza-associated deaths reported among children aged 18 years - United States, 2003-04 influenza season. MMWR (2004) 52(53):1286–1288.
  • WRIGHT PF, WEBSTER RG: Orthomyxoviruses . In: Fields Virology Knipe DM Howley PM (Eds), Lippincott Williams & Wilkins, Philadelphia. (2001) 1:1533–1580.
  • •Review of influenza epidemiology, pathogenesis, genetics and control.
  • FOUCHIER RA, SCHNEEBERGER PM, ROZENDAAL FW et al.: Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc. Nati Acad. Sci. USA (2004) 101:1356–1361.
  • STEVENS J, CORPER AL, BASLER CF, TAUBENBERGER JK, PALESE P, WILSON IA: Structure of the uncleaved human H hemagglutinin from the extinct 1918 influenza virus. Science (2004) 303: 1866-1870.
  • •Crystal structure of the 1918 'Spanish flu' virus suggests that only subtle changes to an avian H1 HA may have sufficed to allow efficient human-to-human transmission.
  • WANG T: Recent advances in the discovery and development of anti-influenza drugs. Expert Opin. Ther. Patents (2002) 12:845–861.
  • •Comprehensive review of structure-based NA inhibitor design.
  • HAYDEN FG, OSTERHAUS AD, TREANOR JJ et al.: Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. GG167 Influenza Study Group. N Engl. Med. (1997) 337:874–880.
  • •Clinical efficacy of zanamivir in reducing time to alleviation of influenza symptoms and reducing nasal viral titres.
  • SILAGY CA, CAMPION K: Effectiveness and role of zanamivir in the treatment of influenza infection. Ann. Med. (1999) 31:313–317.
  • MONTO AS, FLEMING DM, HENRY D et al.: Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. I Infect. Dis (1999) 180:254–261.
  • •Clinical efficacy of zanamivir and increased efficacy in patients treated within 30 h of symptom onset.
  • 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: US Oral Neuraminidase Study Group. JAMA (2000) 283:1016–1024.
  • •Clinical efficacy of oseltamivir. A reduced number of patients in the oseltamivir treatment groups received antibacterials compared to the placebo group.
  • NICHOLSON KG, AOKI FY, OSTERHAUS AD et al.: Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet (2000) 355:1845–1850.
  • •Clinical efficacy of oseltamivir.
  • SINGH S, BARGHOORN J, BAGDONAS A et al.: Clinical benefits with oseltamivir in treating influenza in adult populations: results of a pooled and subgroup analysis. Clin . Drug Invest. (2003) 23:561–569.
  • •Pooled analysis of oseltamivir efficacy from ten randomised, double-blind studies.
  • GOVORKOVA EA, LENEVA IA, GOLOUBEVA OG, BUSH K, WEBSTER RG: Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Antimicrob . Agents Chemother: (2001) 45:2723–2732.
  • •Efficacy of NA inhibitors against all nine NA subtypes in vitro and against lethal infection with H5N1 and H9N2 viruses in mice .
  • LENEVA IA, ROBERTS N, GOVORKOVA EA, GOLOUBEVA OG, WEBSTER RG: The neuraminidase inhibitor GS-4104 (oseltamivir phosphate) is efficacious against A/Hong Kong/156/97 (H5N1) and A/Hong Kong/1074/99 (H9N2) influenza viruses. Antiviral Res. (2000) 48:101–115.
  • •Efficacy of oseltamivir against avian viruses isolated from humans in Hong Kong during outbreaks in 1997 and 1999.
  • GUBAREVA LV, PENN CR, WEBSTER RG: Inhibition of replication of avian influenza viruses by the neuraminidase inhibitor 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid. Virology (1995) 212:323–330.
  • PEGG MS, VON ITZSTEIN M: Slow-binding inhibition of sialidase from influenza virus. Biochem. Mol. Biol. Int. (1994) 32:851–858.
  • KATI WM, SALDIVAR AS, MOHAMADI F, SHAM HL, LAVER WG, KOHLBRENNER WE: GS-4071 is a slow-binding inhibitor of influenza neuraminidase from both A and B strains. Biochem. Biophys. Res. Commun. (1998) 244:408–413.
  • KIM CU, LEW W, WILLIAMS MA et al.: Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. Am . Chem. Soc. (1997) 119:681–690.
  • •Discovery of cydohexene-based NA inhibitors.
  • LEW W, CHEN X, KIM CU: Discoveryand development of GS 4104 (oseltamivir): an orally active influenza neuraminidase inhibitor. Curr. Med. Chem. (2000) 7:663–672.
  • BABU YS, CHAND P, BANTIA S et al.:BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. j Med. Chem. (2000) 43:3482–3486.
  • •Discovery of cydopentane-based NA inhibitors.
  • SID WELL RW, SMEE DF: Peramivir (BCX-18-12, RWJ-270201): potential new therapy for influenza. Expert Opin. Investig. Drugs (2002) 11:859–869.
  • •Summary of perarnivir activity in vitro and in the influenza mouse model.
  • KATI WM, MONTGOMERY D, CARRICK R et al.: In vitro characterization of A-315675, a highly potent inhibitor of A and B strain influenza virus neuraminidases and influenza virus replication. Antimicrob. Agents Chemother: (2002) 46:1014–1021.
  • •Biological activities of the Abbott pyrrolidine NA inhibitor lead and determination of NA binding affinities.
  • HONDA T, MASUDA T, YOSHIDA S, ARAI M, KOBAYASHI Y, YAMASHITA M: Synthesis and anti-influenza virus activity of 4-guanidino-7-substituted Neu5Ac2en derivatives. Bioorg. Med. Chem. Lett. (2002) 12:1921–1924.
  • YAMASHITA M, OHNO A, TOM OZAWA T, YOSHIDA S: R-118958, a unique anti-influenza agent: a prodrug form of R-125489, a novel inhibitor of influenza virus neuraminidase. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, USA. Sep 14–17 (2003) Poster F–1829.
  • NAKAI N, OITATE M, HOSHI M, KOBAYASHI N, YAMAMURA N, HIROTA T: R118958, a unique anti-influenza agent: pharmacokinetics and metabolism after intranasal/intratracheal administration to rats and mice. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, USA. Sep 14–17 (2003) Poster F–1833.
  • YAMASHITA M, OHNO A, TOM OZAWA T, YOSHIDA S: R-118958, a unique anti-influenza agent: single administration shows high efficacy for both prophylaxis and treatment. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, USA, Sep 14–17 (2003) Poster F–1830.
  • RENNECKE J, HIROTA T, PUCHLER K: R-118958, a unique anti-influenza agent: safety, tolerability and pharmacokinetics in healthy male volunteers. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, USA. Sep 14–17 (2003) Poster F–1834.
  • PATTON JS: Mechanisms of macromolecule absorption by the lungs. Adv. Drug Deify. Rev (1996) 19:3–36.
  • BYRON PR, PATTON JS: Drug delivery via the respiratory tract. J. Aerosol. Med. (1994) 7:49–75.
  • HONDA T, YOSHIDA S, ARAI M, MASUDA T, YAMASHITA M: Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives. Bioorg. Med. Chem. Lett. (2002) 12:1929–1932.
  • •In vitro and mouse model efficacy of polyvalent zanamivir analogues.
  • MASUDA T, YOSHIDA S, ARAI M, KANEKO S, YAMASHITA M, HONDA T: Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives. Chem. Pharm. Bull. (Tokyo) (2003) 51:1386–1398.
  • WATSON KG, CAMERON R, FENTON RI et al.: Highly potent and long-acting trimeric and tetrameric inhibitors of influenza virus neuraminidase. Bioorg. Med. Chem. Lett. (2004) 14:1589–1592.
  • •In vitro and mouse model efficacy of zanamivir trimers and tetramers is higher than that of monomeric zanamivir.
  • DIGGORY P, FERNANDEZ C, HUMPHREY A, JONES V, MURPHY M: Comparison of elderly people's technique in using two dry powder inhalers to deliver zanamivir: randomised controlled trial. Br. Med. J. (2001) 322:577–579.
  • MASUDA T, SHIBUYA S, ARAI M et al.:Synthesis and anti-influenza evaluation of orally active bicyclic ether derivatives related to zanamivir. Bioorg. Med. Chem. Lett. (2003) 13:669–673.
  • •First report of orally-active zanamivir analogues.
  • LAMB RA, KRUG RM: Orthomyxoviridae : the viruses and their replication. In: Fields Virology Knipe DM, Howley PM (Eds), Lippincott Williams & Wilkins. Philadelphia (2001):1487–1532.
  • •Comprehensive review of influenza virus structure, replication and genetics.
  • DOAN L, HANDA B, ROBERTS NA, KLUMPP K: Metal ion catalysis of RNA cleavage by the influenza virus endonuclease. Biochemistry (1999) 38:5612–5619.
  • LEE MT, KLUMPP K, DIGARD P, TILEY L: Activation of influenza virus RNA polymerase by the 5' and 3' terminal duplex of genomic RNA. Nucleic Adds Res. (2003) 31:1624–1632.
  • PARKES KE, ERMERT P, FASSLER J et al.: Use of a pharmacophore model to discover a new class of influenza endonuclease inhibitors. J. Med. Chem. (2003) 46:1153–1164.
  • TOMASSINI J, SELNICK H, DAVIES ME et al: Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds. Antimicrob. Agents Chemother: (1994) 38:2827–2837.
  • HASTINGS JC, SELNICK H: WOLANSKI B, TOMASSINI JE: Anti-influenza virus activities of 4-substituted 2,4-dioxobutanoic acid inhibitors. Antimicrob. Agents Chemother. (1996) 40:1304–1307.
  • •First demonstration of in vivo mouse model efficacy of an influenza endonuclease inhibitor.
  • SINGH SB, TOMASSINI JE: Synthesis of natural flutimide and analogous fully substituted pyrazine-2, 6-diones, endonuclease inhibitors of influenza virus. Org. Chem. (2001) 66:5504–5516.
  • TOMASSINI JE, DAVIES ME, HASTINGS JC et al.: A novel antiviral agent which inhibits the endonuclease of influenza viruses. Antimicrob. Agents Chemother: (1996) 40:1189–1193.
  • KLUMPP K, HANG JQ, RAJENDRAN S et al.: Two-metal ion mechanism of RNA cleavage by HIV RNase H and mechanism-based design of selective HIV RNase H inhibitors. Nucleic Adds Res. (2003) 31:6852–6859.
  • CHUNG TD, CIANCI C, HAGEN M et al.: Biochemical studies on capped RNA primers identify a class of oligonucleotide inhibitors of the influenza virus RNA polymerase. Proc. Natl. Acad. Sci. USA (1994) 91:2372–2376.
  • CIANCI C, COLONNO RI, KRYSTAL M: Differential effect of modified capped RNA substrates on influenza virus transcription. Virus Res. (1997) 50:65–75.
  • KLUMPP K, DOAN L, ROBERTS NA, HANDA B: RNA and DNA hydrolysis are catalyzed by the influenza virus endonuclease. J. Biol. Chem. (2000) 275:6181–6188.
  • TADO M, ABET, HATTA T et al: Inhibitory effect of modified 5'-capped short RNA fragments on influenza virus RNA polymerase gene expression. Antivir: Chem. Chemother. (2001) 12:353–358.
  • HOOKER L, SULLY R, HANDA B, ONO N, KOYANO H, KLUMPP K: Quantitative analysis of influenza virus RNP interaction with RNA cap structures and comparison to human cap binding protein eIF4E. Biochemistry (2003) 42:6234–6240.
  • •First demonstration of influenza specific cap-binding inhibition by a small molecule.
  • YANG SH, SHARROCKS AD, WHITMARSH Al: Transcriptional regulation by the MAP kinase signaling cascades. Gene (2003) 320:3–21.
  • •Recent review of MAPK signalling pathways.
  • PLESCHKA S: WOLFF T, EHRHARDT C et al.: Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Nat. Cell Bid. (2001) 3:301–305.
  • •Demonstration of importance of the host kinase MEK for influenza replication and RNP nuclear export.
  • LUDWIG S, WOLFF T, EHRHARDT C et al.: MEK inhibition impairs influenza B virus propagation without emergence of resistant variants. FEBS Lett. (2004) 561:37–43.
  • ALLEN LF, SEBOLT-LEOPOLD J, MEYER MB: CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin. Oncol (2003) 30:105–116.
  • •Review of in vivo activities of a selective MEK1/MEK2 inhibitor.
  • FAVATA ME HORIUCHI KY, MANOS EJ et al.: Identification of a novel inhibitor of mitogen-activated protein kinase kinase. Biol Chem. (1998) 273:18623–18632.
  • SEBOLT-LEOPOLD JS, DUDLEY DT, HERRERA R et al.: Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat. Med. (1999) 5:810–816.
  • •First demonstration of in vivo antiturnour activity of a MEK inhibitor.
  • SEGER R, AHN NG, POSADA J et al: Purification and characterization of mitogen-activated protein kinase activator(s) from epidermal growth factor-stimulated A431 cells. Biol. Chem. (1992) 267:14373–14381.
  • WITYAK J, HOBBS FW, GARDNER DS et al.: Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors. Bioorg. Med. Chem. Lett. (2004) 14:1483–1486.
  • WATERHOUSE DM, RINEHART J, ADJEI AA, HECHT JR, NATALE RB, AL E: A Phase II study of an oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon or pancreatic cancer. 39th Annual Meeting of the American Socieo, of Clinical Oncology (2003) Abstracts 204 and 816.
  • MEHTA A, OUZOUNOV S, JORDAN R et al.: Imino sugars that are less toxic but more potent as antivirals, M vitro, compared with N-n-nonyl DNJ. Antivir. Chem. Chemother. (2002) 13:299–304.
  • •ER glucosidase inhibitors as antiviral agents.
  • JORDAN R, NIKOLAEVA OV, WANG L et al.: Inhibition of host ER glucosidase activity prevents Golgi processing of virion-associated bovine viral diarrhea virus E2 glycoproteins and reduces infectivity of secreted virions. Virology (2002) 295:10–19.
  • BLOCK TM, JORDAN R: Iminosugars aspossible broad spectrum anti hepatitis virus agents: the glucovirs and alkovirs. Anti vir. Chem. Chemother. (2001) 12:317–325.
  • ROTH H, MCPHERSON M, HAMEDANI P, AL E: Phase I tolerance and pharmacokinetics of a new castanospermine derivative, MDL-28574A. I I th International Conference on AIDS (1996) Abstract 284.
  • FURUTA Y, TAKAHASHI K, FUKUDA Y et al.: ha vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob. Agents Chernother. (2002) 46:977–981.
  • TAKAHASHI K, FURUTA Y, FUKUDA Y et al.: In vitro and in vivo activities of T-705 and oseltamivir against influenza virus. Antivir. Chem. Chemother. (2003) 14:235–241.
  • •First report of a new, potential nucleoside inhibitor of influenza virus replication.
  • STREETER DG, MILLER JP, ROBINS RK, SIMON LN: The enzymic conversion of 1,2,4-triazole-3-carboxamide to ribavirin-5'-phosphate and its relationship to the proposed mechanism of action. Ann. NY Acad. Sci. (1977) 284:201–210.
  • AOKI FY, MACLEOD MD, PAGGIARO P et al: Early administration of oral oseltamivir increases the benefits of influenza treatment.' Antimicrob. Chemother. (2003) 51:123–129.
  • •Earlier start of treatment with oseltamivir is associated with increased efficacy. Demonstrated reliable influenza diagnosis by physicians even at early times after symptom onset.
  • TISDALE M, APPLEYARD G, TUTTLE J et al.: Inhibition of influenza A and B viruses by 2'-deoxy-2'-fluororibosides. Antiviral Chem.Chemother. (1993) 4:281–287.
  • •In vitro and in vivo mouse model efficacy of anti-influenza nucleoside inhibitors.
  • TISDALE M, ELLIS M, KLUMPP K, COURT S, FORD M: Inhibition of Influenza virus transcription by 2'-deoxy-2'-fluoroguanosine. Antimicrob. Agents Chemother. (1995) 39: 2454–2458.
  • ROBERTS NA: Anti-influenza drugs and neuraminidase inhibitors. Frog. Drug Res. (2001) 56:195–237.
  • ROBERTS NA: Treatment of influenza with neuraminidase inhibitors: virological implications. Phil. Trans. R. Soc. Lond. B Biol. Sci. (2001) 356:1895–1897.
  • MCKIMM-BRESCHKIN J, TRIVEDI T, HAMPSON A et al.: Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob. Agents Chemother. (2003) 47:2264–2272.
  • GUBAREVA LV, WEBSTER RG, HAYDEN FG: Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants. Antimicrob. Agents Chemother. (2001) 45:3403–3408.
  • TAYLOR DL, KANG MS, BRENNAN TM, BRIDGES CG, SUNKARA PS, TYMS AS: Inhibition of a-glucosidase I of the glycoprotein-processing enzymes by 6-0-butanoyl castanospermine (MDL-28574) and its consequences in human immunodeficiency virus-infected T cells. Antimicrob. Agents Chemother. (1994) 38:1780–1787.
  • HERLOCHER ML, CARR J, IVES J et al:Influenza virus carrying an R292K mutation in the neuraminidase gene is not transmitted in ferrets. Antiviral Res. (2002) 54:99–111.

Websites

  • http://www.cdc.gov/nchs/fastats/lcod.htm US Department of Health and Human Services — National Center for Health Statistics: Deaths — Leading Causes. (2004).
  • http://www.biocryst.com Biocryst Pharmaceuticals, Inc.: Announces Preliminary Phase III Trial Results for Influenza Neuraminidase Inhibitor. Media Release 25 June (2002).
  • http://www.cdc.gov/flu/professionals/antivira lback.htm Centers for Disease Control and Prevention: antiviral agents for influenza: background information for clinicians (2003).
  • http://www.mbiotech.com/invest_nr.html. Micrologix press release: Micrologix acquires clinical-stage hepatitis C drug candidate. Micrologix corporate website (2004).

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