Extreme Multidrug Resistant HIV-1 Protease with 20 Mutations Is Resistant to Novel Protease Inhibitors with P1鈥?Pyrrolidinone or P2-Tris-tetrahydrofuran

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• 作者：Johnson Agniswamy ; Chen-Hsiang Shen ; Yuan-Fang Wang ; Arun K. Ghosh ; Kalapala Venkateswara Rao ; Chun-Xiao Xu ; Jane M. Sayer ; John M. Louis ; Irene T. Weber
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 23, 2013
• 年：2013
• 卷：56
• 期：10
• 页码：4017-4027
• 全文大小：581K
• 年卷期：v.56,no.10(May 23, 2013)
• ISSN：1520-4804

文摘

Extreme drug resistant mutant of HIV-1 protease (PR) bearing 20 mutations (PR20) has been studied with the clinical inhibitor amprenavir (1) and two potent antiviral investigational inhibitors GRL-02031 (2) and GRL-0519 (3). Clinical inhibitors are >1000-fold less active on PR20 than on wild-type enzyme, which is consistent with dissociation constants (K_L) from isothermal titration calorimetry of 40 nM for 3, 178 nM for amprenavir, and 960 nM for 2. High resolution crystal structures of PR20鈥搃nhibitor complexes revealed altered interactions compared with the corresponding wild-type PR complexes in agreement with relative inhibition. Amprenavir lacks interactions due to PR20 mutations in the S2/S2鈥?subsites relative to PR. Inhibitors 2 and 3 lose interactions with Arg8鈥?in PR20 relative to the wild-type enzyme because Arg8鈥?shifts to interact with mutated L10F side chain. Overall, inhibitor 3 compares favorably with darunavir in affinity for PR20 and shows promise for further development.