Development of broad spectrum Hepatitis C Virus NS3/4A protease inhibitors

DESCRIPTION provided by applicant This is a collaborative proposal to develop inhibitors with reduced susceptibility to resistance and improved genotype spectrum of activity against the NS A protease of the Hepatitis C virus HCV Over three percent of the worldandapos s population is infected with the hepatitis C virus HCV Unfortunately the current best treatment is still quite challenging against the most prevalent genotype The HCV NS A protease is an attractive drug target due to its essential role in viral replication In prior work we discovered two novel scaffolds that show inhibitory activity against four of the most prevalent genotypes one of which shows an IC value of M against wild type NS genotype b and also maintained its potency within a fold range against five drug resistant mutants Another with an IC of M against the more common genotypes will provide a backup hit We propose to develop these scaffolds into a low molecular weight NS A inhibitor with broader spectrum activity and fewer side effects than current therapeutics We will pursue this goal through three targeted aims to utilize scaffold expansion of current hits to develop more extensive Structure Activity Relationships SARs to increase potency by at least an order of magnitude use structure based design and synthesis to further improve inhibitors and utilize metabolic stability and related pharmacokinetic parameters along with HCV antiviral efficacy to iteratively improve inhibitor design therapeutic characteristics With these Aims we expect to attain Milestone criteria for success that include reducing the inhibitor enzymatic IC to nM obtaining antiviral EC nM replicon assay retaining good enzymatic selectivity for NS A vs other off target enzymes mouse microsomal stability t andgt min potential for good oral bioavailability and minimal cytotoxicity with a selectivity index SI PUBLIC HEALTH RELEVANCE Hepatitis C virus HCV is a major cause of chronic liver diseases and hepatocellular carcinoma affecting more than million people of world population There are million new infections each year with more than annual deaths from HCV related liver diseases Our research will utilize a combination of computational chemistry enzymology X ray crystallography synthetic medicinal chemistry mutational resistance analysis and preclinical biological studies to develop inhibitors of an enzyme that is essential for Hepatitis C infection and replication We are developing these as a new potential antiviral therapeutic for the treatment of Hepatitis C