title: Molecular targets for flavivirus drug discovery.
abstract: Flaviviruses are a major cause of infectious disease in humans. Dengue virus causes an estimated 50 million cases of febrile illness each year, including an increasing number of cases of hemorrhagic fever. West Nile virus, which recently spread from the Mediterranean basin to the Western Hemisphere, now causes thousands of sporadic cases of encephalitis annually. Despite the existence of licensed vaccines, yellow fever, Japanese encephalitis and tick-borne encephalitis also claim many thousands of victims each year across their vast endemic areas. Antiviral therapy could potentially reduce morbidity and mortality from flavivirus infections, but no effective drugs are currently available. This article introduces a collection of papers in Antiviral Research on molecular targets for flavivirus antiviral drug design and murine models of dengue virus disease that aims to encourage drug development efforts. After reviewing the flavivirus replication cycle, we discuss the envelope glycoprotein, NS3 protease, NS3 helicase, NS5 methyltransferase and NS5 RNA-dependent RNA polymerase as potential drug targets, with special attention being given to the viral protease. The other viral proteins are the subject of individual articles in the journal. Together, these papers highlight current status of drug discovery efforts for flavivirus diseases and suggest promising areas for further research.
authors.affiliation: National Center for Natural Product Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
authors.forename: Aruna
authors.initials: A
authors.lastname: Sampath
authors.forename: R
authors.initials: R
authors.lastname: Padmanabhan
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D055808:Drug Discovery; D005416:Flavivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018177:Flavivirus Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology*; D016679:Genome, Viral; D006801:Humans; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins
references.citation: Traffic. 2005 Nov;6(11):967-77
references.pmid: 16190978
references.citation: J Virol. 1993 Nov;67(11):6797-807
references.pmid: 8411382
references.citation: Int J Biochem Cell Biol. 2007;39(3):606-14
references.pmid: 17188926
references.citation: J Biol Chem. 2007 Mar 23;282(12):8873-82
references.pmid: 17276984
references.citation: J Gen Virol. 2007 Aug;88(Pt 8):2223-2227
references.pmid: 17622626
references.citation: J Virol. 2005 Oct;79(20):13105-15
references.pmid: 16189012
references.citation: J Virol. 1991 Nov;65(11):6042-50
references.pmid: 1833562
references.citation: Science. 2008 Mar 28;319(5871):1834-7
references.pmid: 18369148
references.citation: J Biol Chem. 2004 Nov 19;279(47):48535-42
references.pmid: 15322074
references.citation: Science. 2008 Mar 28;319(5871):1830-4
references.pmid: 18369147
references.citation: Curr Opin Infect Dis. 2001 Feb;14(1):13-6
references.pmid: 11979109
references.citation: J Virol Methods. 2001 Mar;92(1):37-44
references.pmid: 11164916
references.citation: Virology. 2006 Mar 1;346(1):53-65
references.pmid: 16325883
references.citation: J Biol Chem. 2004 Mar 26;279(13):12141-51
references.pmid: 14699096
references.citation: Antiviral Res. 2007 Dec;76(3):222-31
references.pmid: 17662475
references.citation: Antivir Ther. 2008;13 Suppl 1:31-6
references.pmid: 18432161
references.citation: Antiviral Res. 2008 Oct;80(1):1-10
references.pmid: 18571739
references.citation: Chem Biol Drug Des. 2006 Jan;67(1):13-26
references.pmid: 16492145
references.citation: J Biol Chem. 2005 Jun 24;280(25):23698-708
references.pmid: 15855154
references.citation: Biochem Biophys Res Commun. 2005 May 20;330(4):1237-46
references.pmid: 15823576
references.citation: Science. 1985 Aug 23;229(4715):726-33
references.pmid: 4023707
references.citation: J Biol Chem. 2001 Dec 7;276(49):45762-71
references.pmid: 11581268
references.citation: Curr Issues Mol Biol. 2007 Jan;9(1):1-20
references.pmid: 17263143
references.citation: Virology. 1989 Aug;171(2):637-9
references.pmid: 2548336
references.citation: AIDS Patient Care STDS. 2008 Jun;22(6):449-57
references.pmid: 18479202
references.citation: Expert Opin Investig Drugs. 2007 Jan;16(1):11-23
references.pmid: 17155850
references.citation: J Virol. 1997 Dec;71(12):9608-17
references.pmid: 9371625
references.citation: Arch Virol. 1993;128(1-2):111-21
references.pmid: 8418788
references.citation: Protein Pept Lett. 2003 Feb;10(1):19-26
references.pmid: 12625822
references.citation: J Virol. 2005 Aug;79(16):10268-77
references.pmid: 16051820
references.citation: J Antimicrob Chemother. 2007 Nov;60(5):981-6
references.pmid: 17872917
references.citation: J Virol. 2007 Oct;81(20):11256-66
references.pmid: 17686844
references.citation: J Virol. 2006 Sep;80(17):8362-70
references.pmid: 16912287
references.citation: Antiviral Res. 2008 Apr;78(1):9-25
references.pmid: 18313769
references.citation: Virology. 1987 Apr;157(2):330-7
references.pmid: 3029975
references.citation: Virology. 1993 Apr;193(2):888-99
references.pmid: 8460492
references.citation: J Virol. 2005 Aug;79(16):10278-88
references.pmid: 16051821
references.citation: J Virol. 2006 Jul;80(13):6686-90
references.pmid: 16775356
references.citation: Biochem J. 2006 Jan 15;393(Pt 2):503-11
references.pmid: 16229682
references.citation: Protein Expr Purif. 2007 May;53(1):87-96
references.pmid: 17174105
references.citation: Antimicrob Agents Chemother. 2008 Sep;52(9):3385-93
references.pmid: 18606844
references.citation: Curr Opin Infect Dis. 2001 Dec;14(6):757-64
references.pmid: 11964896
references.citation: Arch Biochem Biophys. 2007 Jan 15;457(2):187-96
references.pmid: 17184724
references.citation: Arch Virol. 1992;125(1-4):177-91
references.pmid: 1322651
references.citation: J Biol Chem. 2001 May 11;276(19):15581-91
references.pmid: 11278787
references.citation: Bioorg Med Chem. 2007 Dec 15;15(24):7795-802
references.pmid: 17888664
references.citation: J Virol. 1999 Apr;73(4):3108-16
references.pmid: 10074162
references.citation: Virology. 2008 Apr 10;373(2):426-36
references.pmid: 18201743
references.citation: Biochemistry. 2005 Jul 19;44(28):9637-44
references.pmid: 16008349
references.citation: J Virol. 2004 Aug;78(15):8078-84
references.pmid: 15254179
references.citation: J Med Chem. 2006 Nov 2;49(22):6585-90
references.pmid: 17064076
references.citation: Arch Virol. 1996;141(3-4):685-99
references.pmid: 8645104
references.citation: Virology. 1999 May 25;258(1):108-17
references.pmid: 10329573
references.citation: J Virol. 2008 Jan;82(1):173-83
references.pmid: 17942558
references.citation: J Virol. 2001 Nov;75(22):10787-99
references.pmid: 11602720
references.citation: Antimicrob Agents Chemother. 2007 Mar;51(3):845-51
references.pmid: 17194832
references.citation: J Biol Chem. 1999 Nov 19;274(47):33714-22
references.pmid: 10559263
references.citation: J Biol Chem. 2007 Apr 6;282(14):10678-89
references.pmid: 17287213
references.citation: Virology. 2006 Jul 20;351(1):145-58
references.pmid: 16631221
references.citation: J Virol. 2007 May;81(9):4881-5
references.pmid: 17301152
references.citation: J Virol. 1993 Oct;67(10):6152-8
references.pmid: 8396675
references.citation: Nat Med. 2004 Dec;10(12 Suppl):S98-109
references.pmid: 15577938
references.citation: J Virol. 2007 Apr;81(8):4381-5
references.pmid: 17287285
references.citation: J Virol. 2008 May;82(10):4731-41
references.pmid: 18337583
references.citation: J Biol Chem. 2001 Oct 26;276(43):39926-37
references.pmid: 11546770
references.citation: Eur J Biochem. 2003 Apr;270(8):1645-53
references.pmid: 12694177
references.citation: J Biol Chem. 2007 Apr 27;282(17):12883-92
references.pmid: 17337448
references.citation: Proc Natl Acad Sci U S A. 1990 Nov;87(22):8898-902
references.pmid: 2147282
references.citation: J Biochem Mol Biol. 2002 Mar 31;35(2):206-12
references.pmid: 12297031
references.citation: Nat Struct Mol Biol. 2006 Apr;13(4):372-3
references.pmid: 16532006
references.citation: J Gen Virol. 2001 Apr;82(Pt 4):735-745
references.pmid: 11257177
references.citation: J Virol. 2007 May;81(9):4753-65
references.pmid: 17301146
references.citation: J Virol. 1997 Jan;71(1):291-8
references.pmid: 8985349
references.citation: Antivir Chem Chemother. 2007;18(2):103-9
references.pmid: 17542155
references.citation: J Virol. 1990 Sep;64(9):4364-74
references.pmid: 2143543
references.citation: Antiviral Res. 2008 Apr;78(1):1-8
references.pmid: 18243346
references.citation: Bioorg Med Chem Lett. 2006 Jan 1;16(1):40-3
references.pmid: 16246563
references.citation: J Virol. 2006 May;80(9):4623-32
references.pmid: 16611922
references.citation: Virology. 1998 Jun 5;245(2):203-15
references.pmid: 9636360
references.citation: J Virol. 2007 Jun;81(12):6471-81
references.pmid: 17526891
references.citation: Protein Sci. 2007 May;16(5):795-806
references.pmid: 17400917
references.citation: J Biol Chem. 2006 Feb 24;281(8):4624-37
references.pmid: 16371364
references.citation: J Exp Med. 2005 Nov 7;202(9):1179-84
references.pmid: 16260489
references.citation: J Virol. 2005 Jul;79(13):8004-13
references.pmid: 15956546
references.citation: J Med Chem. 2003 Sep 11;46(19):4149-64
references.pmid: 12954067
references.citation: J Virol. 2007 May;81(9):4501-9
references.pmid: 17301157
references.citation: Nat Rev Microbiol. 2005 Jan;3(1):13-22
references.pmid: 15608696
references.citation: J Virol. 2003 Jun;77(12):7131-8
references.pmid: 12768034
references.citation: Curr Med Chem. 2006;13(17):2003-20
references.pmid: 16842194
references.citation: Bioorg Med Chem. 2006 Dec 15;14(24):8396-404
references.pmid: 17010618
references.citation: Mol Pharmacol. 2006 Apr;69(4):1461-7
references.pmid: 16421290
references.citation: Biochem J. 2007 Feb 1;401(3):743-52
references.pmid: 17067286
references.citation: J Biol Chem. 2005 Aug 5;280(31):28766-74
references.pmid: 15932883
references.citation: Virology. 1993 Mar;193(1):1-10
references.pmid: 8382392
references.citation: J Virol. 1991 May;65(5):2467-75
references.pmid: 2016768
references.citation: J Mol Biol. 2007 Sep 21;372(3):723-36
references.pmid: 17686489
references.citation: J Biol Chem. 2003 Jul 4;278(27):24388-98
references.pmid: 12700232
references.citation: Microbes Infect. 2002 Nov;4(13):1301-7
references.pmid: 12443894
references.citation: J Gen Virol. 2006 Oct;87(Pt 10):2755-2766
references.pmid: 16963734
references.citation: Protein Expr Purif. 2007 Apr;52(2):334-9
references.pmid: 17189703
references.citation: J Virol. 2008 Jul;82(14):7047-58
references.pmid: 18448528
references.citation: J Virol. 1993 Feb;67(2):989-96
references.pmid: 8380474
references.citation: Recent Pat Antiinfect Drug Discov. 2006 Jan;1(1):45-55
references.pmid: 18221133
references.citation: J Gen Virol. 2002 Dec;83(Pt 12):3093-3102
references.pmid: 12466486
references.citation: J Mol Med (Berl). 2002 Feb;80(2):86-95
references.pmid: 11907645
references.citation: Assay Drug Dev Technol. 2007 Dec;5(6):737-50
references.pmid: 18181690
references.citation: Antiviral Res. 2008 Oct;80(1):23-35
references.pmid: 18611413
references.citation: J Virol. 2003 Aug;77(16):8831-42
references.pmid: 12885902
references.citation: Antimicrob Agents Chemother. 2007 Jul;51(7):2642-5
references.pmid: 17452483
references.citation: EMBO J. 2002 Jun 3;21(11):2757-68
references.pmid: 12032088
references.citation: J Biol Chem. 2005 Jan 28;280(4):2896-903
references.pmid: 15494419
references.citation: J Virol. 2007 May;81(9):4412-21
references.pmid: 17301144
references.citation: J Gen Virol. 2008 Mar;89(Pt 3):636-641
references.pmid: 18272753
references.citation: Curr Top Med Chem. 2007;7(13):1273-89
references.pmid: 17627557
references.citation: J Exp Med. 2003 Apr 7;197(7):823-9
references.pmid: 12682107
references.citation: J Biol Chem. 2005 Jul 22;280(29):27412-9
references.pmid: 15917225
references.citation: Virology. 1996 Feb 15;216(2):317-25
references.pmid: 8607261
references.citation: J Biol Chem. 2003 Dec 5;278(49):49164-70
references.pmid: 12966103
references.citation: Antiviral Res. 2008 Apr;78(1):69-78
references.pmid: 18031836
references.citation: Antiviral Res. 2000 Feb;45(2):135-47
references.pmid: 10809022
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3414-9
references.pmid: 14993605
references.citation: J Mol Biol. 2007 Sep 14;372(2):444-55
references.pmid: 17658551
references.citation: Virology. 2004 Oct 25;328(2):208-18
references.pmid: 15464841
references.citation: Antiviral Res. 2004 Aug;63(2):67-77
references.pmid: 15321702
references.citation: J Biol Chem. 1997 Dec 5;272(49):30715-23
references.pmid: 9388208
references.citation: Bioorg Med Chem. 2003 Jun 12;11(12):2551-68
references.pmid: 12757723
references.citation: J Gen Virol. 2006 Sep;87(Pt 9):2605-2614
references.pmid: 16894199
references.citation: Antiviral Res. 2008 Oct;80(1):11-22
references.pmid: 18585795
references.citation: Cell. 2007 Apr 20;129(2):263-75
references.pmid: 17448989
references.citation: J Biol Chem. 2000 Apr 7;275(14):9963-9
references.pmid: 10744671
references.citation: Nucleic Acids Res. 1989 May 25;17(10):3889-97
references.pmid: 2543956
references.citation: J Virol. 2001 Oct;75(20):9633-43
references.pmid: 11559795
references.citation: Antiviral Res. 2008 Nov;80(2):87-93
references.pmid: 18619493
references.citation: Virology. 2008 Apr 25;374(1):170-85
references.pmid: 18234265
references.citation: J Virol. 1993 Apr;67(4):2034-42
references.pmid: 8383225
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6895-900
references.pmid: 11371613
references.citation: J Virol. 2004 Mar;78(6):3178-83
references.pmid: 14990739
references.citation: J Virol. 1992 Dec;66(12):7549-54
references.pmid: 1433530
references.citation: J Virol. 2006 Jan;80(1):149-60
references.pmid: 16352539
references.citation: J Virol. 2003 Jun;77(12):7143-9
references.pmid: 12768036
references.citation: Antimicrob Agents Chemother. 2002 May;46(5):1231-9
references.pmid: 11959550
references.citation: J Virol. 1997 Sep;71(9):6650-61
references.pmid: 9261387
references.citation: Med Chem. 2006 Nov;2(6):577-89
references.pmid: 17105439
references.citation: J Virol. 1995 Feb;69(2):695-700
references.pmid: 7529335
references.citation: J Gen Virol. 2006 Jul;87(Pt 7):1947-1952
references.pmid: 16760396
references.citation: Curr Med Chem. 2007;14(8):883-915
references.pmid: 17430143
references.citation: Res Initiat Treat Action. 2003 Spring;8(2):25-7
references.pmid: 12845775
references.citation: Drug News Perspect. 2003 Jul-Aug;16(6):355-62
references.pmid: 12973446
references.citation: J Biol Chem. 2006 Dec 15;281(50):38448-58
references.pmid: 17052977
references.citation: J Gen Virol. 2001 Jul;82(Pt 7):1647-1656
references.pmid: 11413376
references.citation: J Virol. 1999 Jun;73(6):5201-6
references.pmid: 10233989
references.citation: Antiviral Res. 2008 Nov;80(2):94-101
references.pmid: 18674567
references.citation: J Gen Virol. 1991 Apr;72 ( Pt 4):851-8
references.pmid: 1826736
references.citation: Bioorg Med Chem Lett. 2006 Jan 1;16(1):36-9
references.pmid: 16246553
references.citation: J Med Chem. 2003 Oct 23;46(22):4776-89
references.pmid: 14561097
references.citation: J Virol. 2007 Apr;81(8):3891-903
references.pmid: 17267492
references.citation: J Virol. 1986 Dec;60(3):1113-24
references.pmid: 3023663