Biochemistry

A Viral Turn-Off

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Science  26 Oct 2012:
Vol. 338, Issue 6106, pp. 444-445
DOI: 10.1126/science.338.6106.444-e
CREDIT: S. M. SAALAU-BATHELL ET AL., NAT. CHEM. BIOL. (30 SEPTEMBER 2012) © 2012 NPG/ASTEX PHARMACEUTICALS

Chronic hepatitis C virus (HCV) infection is a major cause of liver failure. The NS3 protein of HCV has been aggressively pursued as a drug target because it is involved in viral polyprotein processing, through a serine protease domain, and in viral replication, through a helicase domain. Moreover, two drugs targeting the protease domain were approved in 2011, but more are needed. To identify new inhibitors, Saalau-Bethell et al. performed a fragment-based screen using crystals of the NS3 protein bound to NS4a (a peptide cofactor). Binding was detected at the interface of the protease and helicase domains, and the low-affinity fragments were elaborated into tight binding leads. The tightest binder had Kd = 0.02 µM, exhibited antiviral activity, and inhibited protease activity of the full-length protein, but not the isolated protease domain. Part of the NS3 helicase domain has been shown to bind the active site of the protease domain, and two species consistent with closed and open conformations have been suggested. The authors propose that inhibitors that bind at the NS3 domain interface shift the equilibrium toward the closed state, thereby inhibiting protease activity through a noncompetitive mechanism and probably helicase activity, too.

Nat. Chem. Biol. 10.1038/NCHEMBIO.1081 (2012).

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