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HTS-Driven Discovery of New Chemotypes with West Nile Virus Inhibitory Activity
Department of Biochemistry and Molecular Biology, Southern Research Institute, 2000 9th Ave S. Birmingham, AL 35205, USA
Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, Department of Microbiology and Immunology, 505. S. Hancock, University of Louisville, KY 40222, USA
Southern Research Institute, 431 Aviation Way, Frederick, MD 21701, USA
Division of Infectious Disease, 1900 University Boulevard, THT 229, University of Alabama at Birmingham, AL 35294, USA
* Author to whom correspondence should be addressed.
Received: 25 January 2010; in revised form: 20 February 2010 / Accepted: 8 March 2010 / Published: 12 March 2010
Abstract: West Nile virus (WNV) is a positive sense, single-stranded RNA virus that can cause illness in humans when transmitted via mosquito vectors. Unfortunately, no antivirals or vaccines are currently available, and therefore efficient and safe antivirals are urgently needed. We developed a high throughput screen to discover small molecule probes that inhibit virus infection of Vero E6 cells. A primary screen of a 13,001 compound library at a 10 µM final concentration was conducted using the 384-well format. Z′ values ranged from 0.54–0.83 with a median of 0.74. Average S/B was 17 and S/N for each plate ranged from 10.8 to 23.9. Twenty-six compounds showed a dose response in the HT screen and were further evaluated in a time of addition assay and in a titer reduction assay. Seven compounds showed potential as small molecule probes directed at WNV. The hit rate from the primary screen was 0.185% (24 compounds out of 13,001 compounds) and from the secondary screens was 0.053% (7 out of 13,001 compounds) respectively.
Keywords: West Nile virus; high throughput screen; antivirals; chemotypes
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Chung, D.H.; Jonsson, C.B.; Maddox, C.; McKellip, S.N.; Moore, B.P.; Heil, M.; White, E.L.; Ananthan, S.; Li, Q.; Feng, S.; Rasmussen, L. HTS-Driven Discovery of New Chemotypes with West Nile Virus Inhibitory Activity. Molecules 2010, 15, 1690-1704.
Chung DH, Jonsson CB, Maddox C, McKellip SN, Moore BP, Heil M, White EL, Ananthan S, Li Q, Feng S, Rasmussen L. HTS-Driven Discovery of New Chemotypes with West Nile Virus Inhibitory Activity. Molecules. 2010; 15(3):1690-1704.
Chung, Dong Hoon; Jonsson, Colleen B.; Maddox, Clinton; McKellip, Sara N.; Moore, Blake. P.; Heil, Marintha; White, E. Lucile; Ananthan, Subramaniam; Li, Qianjun; Feng, Shuang; Rasmussen, Lynn. 2010. "HTS-Driven Discovery of New Chemotypes with West Nile Virus Inhibitory Activity." Molecules 15, no. 3: 1690-1704.