Chronic liver disease kills an estimated 1000 people in the US every year and is caused in 40 percent of cases, by the hepatitis C virus. This virus has a positive strand RNA as its genome and a highly error prone NS5B RNA-dependent RNA polymerase for genomic replication. As a consequence, HCV has rapidly evolved with six genotypes and more than 14 sub-genotypes. Great efforts have been made to develop effective direct acting antivirals (DAA), however, by focusing on genotype 1a, the most predominant in western countries, we have neglected about 30 percent of people infected with HCV and moreover, victims found in third world countries. The heterogeneity of the virus has clearly set limitations to the discovery of a pan-genotypic DAA. That being said, I propose that by understanding the differences in substrate recognition of the most divergent HCV NS3/4A protease, we can get one step closer to designing an inhibitor that satisfies two major properties: 1) the inhibitor must fit within the overall substrate envelope of all HCV NS3/4A protease;2) the inhibitor must exhibit a very low susceptibility to drug resistance. To that end, crystal structures of the protease domain of HCV NS3/4A from various genotypes will be determined in complex with their natural substrates and inhibitors.

Public Health Relevance

Hepatitis C infects an estimated 170 million people worldwide, new drugs called protease inhibitors are coming on the market but are only effective on patients in the west. I plan to study the molecular interactions of these drugs in forms of the virus that predominantly infect the rest of the world, with the hope of developing more effective drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31GM103259-01
Application #
8399476
Study Section
Special Emphasis Panel (ZRG1-F13-C (20))
Program Officer
Gaillard, Shawn R
Project Start
2013-01-24
Project End
2016-01-23
Budget Start
2013-01-24
Budget End
2014-01-23
Support Year
1
Fiscal Year
2013
Total Cost
$28,746
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655