HTS identifies novel and specific uncompetitive inhibitors of the two-component NS2B-NS3 proteinase of West Nile virus.

Abstract:

:West Nile virus (WNV), a member of the Flavividae family, is a mosquito-borne, emerging pathogen. In addition to WNV, the family includes dengue, yellow fever, and Japanese encephalitis viruses, which affect millions of individuals worldwide. Because countermeasures are currently unavailable, flaviviral therapy is urgently required. The flaviviral two-component nonstructural NS2B-NS3 proteinase (protease [pro]) is essential for viral life cycle and, consequently, is a promising drug target. We report here the results of the miniaturization of an NS2B-NS3pro activity assay, followed by high-throughput screening of the National Institutes of Health's 65,000 compound library and identification of novel, uncompetitive inhibitors of WNV NS2B-NS3pro that appear to interfere with the productive interactions of the NS2B cofactor with the NS3pro domain. We anticipate that following structure optimization, the identified probes could form the foundation for the design of novel and specific therapeutics for WNV infection. We also provide the structural basis for additional species-selective allosteric inhibitors of flaviviruses.

journal_name

Assay Drug Dev Technol

authors

Johnston PA,Phillips J,Shun TY,Shinde S,Lazo JS,Huryn DM,Myers MC,Ratnikov BI,Smith JW,Su Y,Dahl R,Cosford ND,Shiryaev SA,Strongin AY

doi

10.1089/adt.2007.101

subject

Has Abstract

pub_date

2007-12-01 00:00:00

pages

737-50

issue

6

eissn

1540-658X

issn

1557-8127

journal_volume

5

pub_type

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