The article wasn't about 790052, more about the process whereby they discovered the target and developed the precursors to 790052.
JOURNAL OF VIROLOGY, Jan. 2010, p. 482–491 Vol. 84, No. 1
0022-538X/10/$12.00 doi:10.1128/JVI.01360-09
Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Identification of Hepatitis C Virus NS5A Inhibitors
Julie A. Lemm,1* Donald O’Boyle II,1 Mengping Liu,1 Peter T. Nower,1 Richard Colonno,1†
Milind S. Deshpande,2‡ Lawrence B. Snyder,2 Scott W. Martin,2 Denis R. St. Laurent,2
Michael H. Serrano-Wu,2§ Jeffrey L. Romine,2 Nicholas A. Meanwell,2 and Min Gao1
Department of Virology,1 and Discovery Chemistry,2 Bristol-Myers Squibb Research & Development, Wallingford, Connecticut
Received 2 July 2009/Accepted 25 September 2009
Using a cell-based replicon screen, we identified a class of compounds with a thiazolidinone core structure
as inhibitors of hepatitis C virus (HCV) replication. The concentration of one such compound, BMS-824, that
resulted in a 50% inhibition of HCV replicon replication was 5 nM, with a therapeutic index of >10,000. The
compound showed good specificity for HCV, as it was not active against several other RNA and DNA viruses.
Replicon cells resistant to BMS-824 were isolated, and mutations were identified. A combination of amino acid
substitutions of leucine to valine at residue 31 (L31V) and glutamine to leucine at residue 54 (Q54L) in NS5A
conferred resistance to this chemotype, as did a single substitution of tyrosine to histidine at amino acid 93
(Y93H) in NS5A. To further explore the region(s) of NS5A involved in inhibitor sensitivity, genotype-specific
NS5A inhibitors were used to evaluate a series of genotype 1a/1b hybrid replicons. Our results showed that,
consistent with resistance mapping, the inhibitor sensitivity domain also mapped to the N terminus of NS5A,
but it could be distinguished from the key resistance sites. In addition, we demonstrated that NS5A inhibitors,
as well as an active-site inhibitor that specifically binds NS3 protease, could block the hyperphosphorylation
of NS5A, which is believed to play an essential role in the viral life cycle. Clinical proof of concept has recently
been achieved with derivatives of these NS5A inhibitors, indicating that small molecules targeting a nontraditional
viral protein like NS5A, without any known enzymatic activity, can also have profound antiviral effects
on HCV-infected subjects.
There is some brief discussion about what NS5A does for the virus, but I think this is not well understood yet.
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