SBIR-STTR Award

Optimizing Hepatitis C virus NS5B Polymerase Inhibitors
Award last edited on: 10/13/2005

Sponsored Program
SBIR
Awarding Agency
NIH : NIAID
Total Award Amount
$600,000
Award Phase
2
Solicitation Topic Code
856
Principal Investigator
Y S Babu

Company Information

BioCryst Pharmaceuticals Inc

4505 Emperor Boulevard Suite 200
Durham, NC 27703
   (919) 859-1302
   info@biocryst.com
   www.biocryst.com
Location: Multiple
Congr. District: 01
County: Durham

Phase I

Contract Number: 1R43AI056877-01
Start Date: 7/5/2003    Completed: 6/30/2005
Phase I year
2003
Phase I Amount
$300,000
The over-all objective of this project is identifying and developing selective nontoxic inhibitors of the hepatitis C virus NS5B polymerase and eventually testing them as therapeutics for chronic hepatitis C. At least four million people in the United States have chronic hepatitis C and the recent NIH Consensus Conference suggested that this number is actually two-three fold greater. The high rate of progression to chronic infection (70-80%), liver disease (>50%), and the worldwide distribution of chronic hepatitis C, makes it a major cause of morbidity and mortality. The production of HCV vaccines is a difficult challenge and an intensive development of molecular based HCV therapeutics should be pursued. A major problem in HCV research has been the development of model systems to study HCV replication and identifying effective molecular based therapeutics. We have developed methods for expressing in E. coli and purifying mg quantities of purified enzymatically active NS5B polymerase protein. In addition, crystal structures of NS5B polymerase have been solved and robust cell based replicon systems can be used to test for inhibition of HCV RNA replication. These developments permit virtual screening of small molecules as candidate NS5B polymerase inhibitors. The specific objectives of this project are: 1) to express and purify sufficient quantities of recombinant HCV NS5B polymerase for in vitro assays and crystal growth studies; 2) To test additional compounds, already identified by structure-based virtual screening, for their ability to directly inhibit the HCV NS5B polymerase using an in vitro assay. These results and current NS5B structural information will be used to further design, synthesize and test modifications of lead compounds; 3) To conduct co-crystal growth studies of NS5B, a template, and an inhibitor with the goal of using this ternary complex structure to design and optimize NS5B polymerase inhibitors.

Public Health Relevance Statement:


Project Terms:
microorganism disease chemotherapy; drug screening /evaluation; drug design /synthesis /production; enzyme inhibitor; virus genetics; protein purification; virus replication; hepatitis C virus; replicon; replicase; recombinant virus; hepatitis C

Phase II

Contract Number: 5R43AI056877-02
Start Date: 7/5/2003    Completed: 6/30/2006
Phase II year
2004
Phase II Amount
$300,000
The over-all objective of this project is identifying and developing selective nontoxic inhibitors of the hepatitis C virus NS5B polymerase and eventually testing them as therapeutics for chronic hepatitis C. At least four million people in the United States have chronic hepatitis C and the recent NIH Consensus Conference suggested that this number is actually two-three fold greater. The high rate of progression to chronic infection (70-80%), liver disease (>50%), and the worldwide distribution of chronic hepatitis C, makes it a major cause of morbidity and mortality. The production of HCV vaccines is a difficult challenge and an intensive development of molecular based HCV therapeutics should be pursued. A major problem in HCV research has been the development of model systems to study HCV replication and identifying effective molecular based therapeutics. We have developed methods for expressing in E. coli and purifying mg quantities of purified enzymatically active NS5B polymerase protein. In addition, crystal structures of NS5B polymerase have been solved and robust cell based replicon systems can be used to test for inhibition of HCV RNA replication. These developments permit virtual screening of small molecules as candidate NS5B polymerase inhibitors. The specific objectives of this project are: 1) to express and purify sufficient quantities of recombinant HCV NS5B polymerase for in vitro assays and crystal growth studies; 2) To test additional compounds, already identified by structure-based virtual screening, for their ability to directly inhibit the HCV NS5B polymerase using an in vitro assay. These results and current NS5B structural information will be used to further design, synthesize and test modifications of lead compounds; 3) To conduct co-crystal growth studies of NS5B, a template, and an inhibitor with the goal of using this ternary complex structure to design and optimize NS5B polymerase inhibitors.

Public Health Relevance Statement:


Project Terms:
microorganism disease chemotherapy; drug screening /evaluation; drug design /synthesis /production; enzyme inhibitor; virus genetics; protein purification; virus replication; hepatitis C virus; replicon; replicase; recombinant virus; hepatitis C