Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors

Journal Article · Wed Jul 22 00:00:00 EDT 2009 · Bioorg. Med. Chem. Lett.

DOI:https://doi.org/10.1016/j.bmcl.2008.03.056· OSTI ID:1007119

Antonysamy, Stephen S; Aubol, Brandon; Blaney, Jeff; Browner, Michelle F; Giannetti, Anthony M; Harris, Seth F; Hébert, Normand; Hendle, Jörg; Hopkins, Stephanie; Jefferson, Elizabeth; Kissinger, Charles; Leveque, Vincent; Marciano, David; McGee, Ethel; Nájera, Isabel; Nolan, Brian; Tomimoto, Masaki; Torres, Eduardo; Wright, Tobi ^[1]

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1. SGX

Non-nucleoside inhibitors of HCV NS5b RNA polymerase were discovered by a fragment-based lead discovery approach, beginning with crystallographic fragment screening. The NS5b binding affinity and biochemical activity of fragment hits and inhibitors was determined by surface plasmon resonance (Biacore) and an enzyme inhibition assay, respectively. Crystallographic fragment screening hits with {approx}1-10 mM binding affinity (K{sub D}) were iteratively optimized to give leads with {approx}200 nM biochemical activity and low {micro}M cellular activity in a Replicon assay.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1007119
• Journal Information: Bioorg. Med. Chem. Lett., Journal Name: Bioorg. Med. Chem. Lett. Journal Issue: (9) ; 05, 2008 Vol. 18; ISSN 0960-894X
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
AFFINITY
BIOCHEMISTRY
ENZYMES
HEPATITIS
INHIBITION
NUCLEOSIDES
PLASMONS
REPLICONS
RESONANCE
RNA POLYMERASES