Integrated Strategies for Identifying Leads That Targetthe NS3 Helicase of the Hepatitis C Virus.

Futuretreatments for individuals infected by the hepatitis C virus(HCV) will likely involve combinations of compounds that inhibit multipleviral targets. The helicase of HCV is an attractive target with noknown drug candidates in clinical trials. Herein we describe an integratedstrategy for identifying fragment inhibitors using structural andbiophysical techniques. Based on an X-ray structure of apo HCV helicaseand in silicoand bioinformatic analyses of HCV variants,we identified that one site in particular (labeled 3 + 4) was themost conserved and attractive pocket to target for a drug discoverycampaign. Compounds from multiple sources were screened to identifyinhibitors or binders to this site, and enzymatic and biophysicalassays (NMR and SPR) were used to triage the most promising ligandsfor 3D structure determination by X-ray crystallography. Medicinalchemistry and biophysical evaluations focused on exploring the mostpromising lead series. The strategies employed here can have generalutility in drug discovery. [ABSTRACT FROM AUTHOR]