Identification of novel small-molecule inhibitors of West Nile virus infection.
West Nile virus (WNV) has spread throughout the United States and Canada and now annually causes a clinical spectrum of human disease ranging from a self-limiting acute febrile illness to acute flaccid paralysis and lethal encephalitis. No therapy or vaccine is currently approved for use in humans. Using high-throughput screening assays that included a luciferase expressing WNV subgenomic replicon and an NS1 capture enzyme-linked immunosorbent assay, we evaluated a chemical library of over 80,000 compounds for their capacity to inhibit WNV replication. We identified 10 compounds with strong inhibitory activity against genetically diverse WNV and Kunjin virus isolates. Many of the inhibitory compounds belonged to a chemical family of secondary sulfonamides and have not been described previously to inhibit WNV or other related or unrelated viruses. Several of these compounds inhibited WNV infection in the submicromolar range, had selectivity indices of greater than 10, and inhibited replication of other flaviviruses, including dengue and yellow fever viruses. One of the most promising compounds, AP30451, specifically blocked translation of a yellow fever virus replicon but not a Sindbis virus replicon or an internal ribosome entry site containing mRNA. Overall, these compounds comprise a novel class of promising inhibitors for therapy against WNV and other flavivirus infections in humans.
Noueiry
Amine O
AO
Apath, LLC, St. Louis, MO 63110, USA.
Olivo
Paul D
PD
Slomczynska
Urszula
U
Zhou
Yi
Y
Buscher
Ben
B
Geiss
Brian
B
Engle
Michael
M
Roth
Robert M
RM
Chung
Kyung Min
KM
Samuel
Melanie
M
Diamond
Michael S
MS
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D014709:Vero Cells; D014901:West Nile Fever / Q000517:prevention & control* / Q000628:therapy*; D014902:West Nile virus / Q000378:metabolism*
D000998:Antiviral Agents; D012333:RNA, Messenger
Antiviral Res. 2005 Jul;67(1):38-45
15919121
J Virol. 2003 Feb;77(4):2578-86
12551996
J Virol. 2006 Oct;80(19):9349-60
16973541
Virol J. 2005;2:53
15985182
Lancet Infect Dis. 2004 Sep;4(9):547-56
15336221
J Med Chem. 2006 Mar 23;49(6):2127-37
16539402
Virology. 2003 Sep 1;313(2):514-24
12954218
J Virol. 2005 May;79(9):5414-20
15827155
J Infect Dis. 2002 Oct 15;186(8):1165-8
12355369
Antivir Chem Chemother. 2004 Mar;15(2):101-9
15185728
Emerg Infect Dis. 2001 Jul-Aug;7(4):650-3
11585527
Am J Trop Med Hyg. 2004 Oct;71(4):493-500
15516648
Nature. 2005 Sep 29;437(7059):764-9
16193056
Emerg Infect Dis. 1999 Sep-Oct;5(5):643-50
10511520
Nat Med. 2000 Dec;6(12):1375-9
11100123
J Infect Dis. 2000 Oct;182(4):1214-7
10979920
Antimicrob Agents Chemother. 1983 Jul;24(1):134-6
6684897
Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):12989-94
9789028
J Virol. 2000 Sep;74(17):7814-23
10933688
J Virol. 2000 Jun;74(11):4957-66
10799569
JAMA. 2003 Jul 23;290(4):524-8
12876096
Emerg Infect Dis. 2005 Aug;11(8):1174-9
16102303
J Virol. 2005 Jul;79(14):8698-706
15994763
Biochem Soc Trans. 2002 Apr;30(2):140-5
12023841
Virology. 2002 Dec 20;304(2):211-21
12504563
J Virol. 2007 Mar;81(6):2614-23
17192305
J Biomol Screen. 1999;4(2):67-73
10838414
J Virol. 2007 Jul;81(13):7061-8
17442713
J Virol. 2005 Feb;79(3):1934-42
15650219
Jpn J Med Sci Biol. 1967 Dec;20 Suppl:103-8
4968625
Antiviral Res. 2005 Feb;65(2):79-85
15708634
J Virol. 2005 Apr;79(8):4599-609
15795246
Antiviral Res. 2003 Mar;58(1):73-9
12719009
Antiviral Res. 2002 Jul;55(1):107-16
12076755
J Virol. 2005 Oct;79(20):12828-39
16188985
J Infect Dis. 2006 Nov 1;194(9):1300-8
17041857
Antimicrob Agents Chemother. 2005 Dec;49(12):4980-8
16304161
J Gen Virol. 2003 May;84(Pt 5):1261-8
12692292
AIDS Rev. 2004 Oct-Dec;6(4):234-43
15700622
Emerg Infect Dis. 2001 Jul-Aug;7(4):759
11585547
Transpl Infect Dis. 2002 Sep;4(3):160-2
12421462
J Virol. 2006 Jul;80(14):6982-92
16809304
Emerg Infect Dis. 2001 Jul-Aug;7(4):675-8
11585531
Science. 1999 Jul 2;285(5424):110-3
10390360
J Infect Dis. 2004 Sep 15;190(6):1084-7
15319857
Antiviral Res. 1990 Mar;13(3):139-49
2353804
Antiviral Res. 2005 Nov;68(2):49-55
16199098
J Virol. 2003 Dec;77(24):13203-13
14645577
Antiviral Res. 1999 Feb;41(1):57-64
10321579
Nature. 1990 Nov 1;348(6296):91-2
2234068
Nat Med. 2005 May;11(5):522-30
15852016
N Engl J Med. 2005 Aug 4;353(5):460-7
16079369
J Infect Dis. 2003 Jul 1;188(1):5-12
12825165
J Virol. 2004 Sep;78(17):9285-94
15308723
J Virol. 2005 Sep;79(17):11457-66
16103196
PLoS Med. 2006 Apr;3(4):e96
16464133
Virology. 2005 Apr 25;335(1):99-105
15823609
Ann Neurol. 2006 Sep;60(3):286-300
16983682
Antimicrob Agents Chemother. 2002 May;46(5):1231-9
11959550
J Neurovirol. 2006 Apr;12(2):129-39
16798674
Antimicrob Agents Chemother. 2000 Apr;44(4):859-66
10722482
J Virol. 2006 Feb;80(3):1340-51
16415011
J Virol. 2005 Jul;79(13):8004-13
15956546
J Virol. 2003 Dec;77(24):12941-9
14645550
J Virol. 2005 Dec;79(23):14606-13
16282460
Virol J. 2005;2:49
15927084
J Virol. 2004 Jul;78(14):7737-47
15220448
J Clin Microbiol. 2000 Mar;38(3):1053-7
10698995
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14333-8
14612562
J Virol. 2005 Nov;79(21):13350-61
16227257
Science. 2000 Dec 8;290(5498):1972-4
11110665
J Virol. 2006 Jul;80(14):7009-19
16809306
N Engl J Med. 2006 Dec 7;355(23):2444-51
17151366
J Virol. 2004 Nov;78(22):12225-35
15507609
Antimicrob Agents Chemother. 2006 Apr;50(4):1320-9
16569847
Antiviral Res. 2006 Jun;70(2):39-50
16724398
J Virol. 2005 Nov;79(22):13924-33
16254328
J Infect Dis. 2005 Apr 1;191(7):1148-54
15747251
Virology. 2001 Oct 25;289(2):297-311
11689052
J Virol. 2007 Feb;81(4):2047-55
17151121
Emerg Infect Dis. 2005 Aug;11(8):1167-73
16102302
J Gen Virol. 2006 Jul;87(Pt 7):1947-52
16760396
Clin Infect Dis. 2005 Mar 1;40(5):764-6
15714427
Emerg Infect Dis. 2005 Sep;11(9):1497-8
16673523
Rev Infect Dis. 1989 May-Jun;11 Suppl 4:S750-61
2546248
J Virol. 2006 Oct;80(19):9424-34
16973548
Emerg Infect Dis. 2002 Jan;8(1):107-8
11749765
Can J Neurol Sci. 2004 May;31(2):194-203
15198443
J Virol. 2005 Feb;79(3):1943-7
15650220
Am J Trop Med Hyg. 1982 May;31(3 Pt 1):548-55
6177259