Critical Effect of Peptide Cyclization on the Potency of Peptide Inhibitors against Dengue Virus NS2B-NS3 Protease

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• 作者：Shaoqiong Xu ; Hua Li ; Xiaoxia Shao ; Chongxu Fan ; Bryan Ericksen ; Jinsong Liu ; Chengwu Chi ; Chunguang Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：55
• 期：15
• 页码：6881-6887
• 全文大小：327K
• 年卷期：v.55,no.15(August 9, 2012)
• ISSN：1520-4804

文摘

Dengue virus (DENV) infection is a serious public health threat worldwide that demands effective treatment. In the search for potent virus protease inhibitors, several cone snail venoms were screened against serotype 2 DENV NS2B-NS3 protease, and one conotoxin, MrIA, was identified to have inhibitory activity. The inhibitory activity was attributed to a disulfide bond-mediated loop, from which rational optimization was made to improve the potency and stability. An eight-residue cyclic peptide inhibitor was finally obtained with high potency (inhibitory constant 2.2 渭M), stability, and cell permeability. This inhibitor can thus serve as a good lead for DENV drug development. In addition, this work highlights the critical effect of peptide cyclization on the potency of oligopeptide inhibitors against DENV protease, which may advance the design of peptide inhibitors for homologous virus proteases.