【摘 要】
：
Dengue virus type 2 (DEN2) NS3 protease is required for the processing of the viral polyprotein and viral maturation.Therefore, the NS3 protease represents a promising target for antiviral drug design
【机 构】
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Laboratory of Molecular Virology, Institute of Molecular Biology and Genetics, Mahidol University, S
【出 处】
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2005 WHTS3rd Annual Congress of International Drug Discovery
论文部分内容阅读
Dengue virus type 2 (DEN2) NS3 protease is required for the processing of the viral polyprotein and viral maturation.Therefore, the NS3 protease represents a promising target for antiviral drug design and development.In this study, we show that the N-terminal cleavage site peptides corresponding to the P l-P6 region (RTSKKR, EVKKQR, FAAGRK and TTSTRR) act as competitive inhibitors of the enzyme, with Ki values ranging from 12 to 67 M.The peptide RTSKKR has the lowest Ki (12.14 M) and was used to analyze shorter peptides including SKKR, KKR, KR, AGRR and GKR.The results show that SKKR, KKR, KR, and GKR act as competitive inhibitors of the enzyme, with Ki values ranging from 22 to 188 M.By using the crystal structure coordinates of the hepatitis C virus NS3/NS4A protease complex, we have developed a homology model of the DEN 2 NS2B(H)-NS3(pro) co-complex.With 2 protein structures and 9 peptide substrates aforementioned, molecular docking has been performed to investigate the substrate binding site of NS3.The results show that the cofactor NS2B(H) induces large structural changes in the NS3 protease.These results offer the prospect of developing potent inhibitors by combinatorial chemistry based on the structure of native cleavage site peptides.
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