Peptide Inhibitors of West Nile NS3 Protease: SAR Study of Tetrapeptide Aldehyde Inhibitors

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• 作者：John E. Knox ; Ngai Ling Ma ; Zheng Yin ; Sejal J. Patel ; Wei-Ling Wang ; Wai-Ling Chan ; K. R. Ranga Rao ; Gang Wang ; Xinyi Ngew ; Viral Patel ; David Beer ; Siew Pheng Lim ; Subhash G. Vasudevan ; Thomas H. Kel
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 2, 2006
• 年：2006
• 卷：49
• 期：22
• 页码：6585 - 6590
• 全文大小：327K
• 年卷期：v.49,no.22(November 2, 2006)
• ISSN：1520-4804

文摘

A series of inhibitors related to the benzoyl-norleucine-lysine-arginine-arginine (Bz-nKRR) tetrapeptidealdehyde was synthesized. When evaluated against the West Nile virus (WNV) NS3 protease, the measuredIC₅₀ ranges from ~1 to 200 es/entities/mgr.gif">M. Concurrently, a modeling study using the recently published crystal structureof the West Nile NS3/NS2B protease complex (pdb code 2FP7) was conducted. We found that the crystalstructure is relevant in explaining the observed SAR for this series of tetrapeptides, with the S1 and S2pockets being the key peptide recognition sites. In general, a residue capable of both es/gifchars/pi.gif" BORDER=0 >-stacking and hydrogenbonding is favored in the S1 pocket, while a positively charged residue is preferred in the S2 pocket. Thisstudy not only confirms the importance of the NS2B domain in substrate-based inhibitor binding of WNV,it also suggests that the crystal structure would provide useful guidance in the drug discovery process ofrelated Flavivirus proteases, given the high degree of homology.