Simultaneously Targeting the NS3 Protease and Helicase Activities for More Effective Hepatitis C Virus Therapy. ACS Chem Biol 2015 Aug 21;10(8):1887-96
Date
05/12/2015Pubmed ID
25961497Pubmed Central ID
PMC4546510DOI
10.1021/acschembio.5b00101Scopus ID
2-s2.0-84939797992 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
This study examines the specificity and mechanism of action of a recently reported hepatitis C virus (HCV) nonstructural protein 3 (NS3) helicase-protease inhibitor (HPI), and the interaction of HPI with the NS3 protease inhibitors telaprevir, boceprevir, danoprevir, and grazoprevir. HPI most effectively reduced cellular levels of subgenomic genotype 4a replicons, followed by genotypes 3a and 1b replicons. HPI had no effect on HCV genotype 2a or dengue virus replicon levels. Resistance evolved more slowly to HPI than telaprevir, and HPI inhibited telaprevir-resistant replicons. Molecular modeling and analysis of the ability of HPI to inhibit peptide hydrolysis catalyzed by a variety of wildtype and mutant NS3 proteins suggested that HPI forms a bridge between the NS3 RNA-binding cleft and an allosteric site previously shown to bind other protease inhibitors. In most combinations, the antiviral effect of HPI was additive with telaprevir and boceprevir, minor synergy was observed with danoprevir, and modest synergy was observed with grazoprevir.
Author List
Ndjomou J, Corby MJ, Sweeney NL, Hanson AM, Aydin C, Ali A, Schiffer CA, Li K, Frankowski KJ, Schoenen FJ, Frick DNAuthor
David N. Frick PhD Associate Professor in the Chimistry & Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
Antiviral AgentsHepacivirus
Hepatitis C
Humans
Models, Molecular
Molecular Targeted Therapy
Oligopeptides
Protease Inhibitors
Viral Nonstructural Proteins
