Peptide inhibitors of West Nile NS3 protease: SAR study of tetrapeptide aldehyde inhibitors
Peptide inhibitors of West Nile NS3 protease: SAR study of tetrapeptide aldehyde inhibitors
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DOI：
10.1021/jm0607606
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发表时间：
2006-11-02
影响因子：
7.3
通讯作者：
Keller, Thomas H.
中科院分区：
文献类型：
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作者：
Knox, John E.;Ma, Ngai Ling;Keller, Thomas H.
合成了一系列与苯甲酰-去亮氨酸-赖氨酸-精氨酸-精氨酸(BZ-NKRR)四肽醛相关的抑制剂。当与西尼罗河病毒(West Nile Virus，WNV)NS3蛋白酶进行比较时，测得的IC50范围为1~200亩M。同时，利用最近公布的西尼罗河病毒NS3/NS2B蛋白酶复合体(PDB代码2FP7)的晶体结构进行了建模研究。我们发现晶体结构与这一系列四肽的SAR相关，S1和S2口袋是关键的肽识别位点。一般来说，在S1口袋中，能够同时具有pi堆积和氢键的残基是有利的，而在S2口袋中，带正电的残基是首选的。本研究不仅证实了NS2B结构域在西尼罗河病毒底物抑制物结合中的重要性，而且由于其高度的同源性，它的晶体结构将为相关的黄病毒蛋白水解酶的药物发现过程提供有用的指导。
A series of inhibitors related to the benzoyl-norleucine-lysine-arginine-arginine (Bz-nKRR) tetrapeptide aldehyde was synthesized. When evaluated against the West Nile virus (WNV) NS3 protease, the measured IC50 ranges from similar to 1 to 200 mu M. Concurrently, a modeling study using the recently published crystal structure of the West Nile NS3/NS2B protease complex (pdb code 2FP7) was conducted. We found that the crystal structure is relevant in explaining the observed SAR for this series of tetrapeptides, with the S1 and S2 pockets being the key peptide recognition sites. In general, a residue capable of both pi-stacking and hydrogen bonding is favored in the S1 pocket, while a positively charged residue is preferred in the S2 pocket. This study 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 of related Flavivirus proteases, given the high degree of homology.