Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex

被引：13

作者：

Ghosh, Arun K. ^{[1
,2
]}

Brindisi, Margherita ^{[1
,2
]}

Nyalapatla, Prasanth R. ^{[1
,2
]}

Takayama, Jun ^{[1
,2
]}

Ella-Menye, Jean-Rene ^{[1
,2
]}

Yashchuk, Sofiya ^{[1
,2
]}

Agniswamy, Johnson ^{[3
]}

Wang, Yuan-Fang ^{[3
]}

Aoki, Manabu ^{[5
,6
]}

Amano, Masayuki ^{[5
,6
]}

Weber, Irene T. ^{[3
,4
]}

Mitsuya, Hiroaki ^{[5
,6
,7
,8
]}

机构：

[1] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA

[2] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA

[3] Georgia State Univ, Dept Biol, POB 4010, Atlanta, GA 30303 USA

[4] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA

[5] Kumamoto Univ Med, Dept Hematol, Kumamoto 8608556, Japan

[6] Kumamoto Univ Med, Dept Infect Dis, Kumamoto 8608556, Japan

[7] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA

[8] Natl Ctr Global Hlth & Med, Res Inst, Dept Refractory Viral Infect, Shinjuku Ku, Tokyo 1628655, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 19期

基金：

美国国家卫生研究院;

关键词：

HIV-1; protease; Drug-resistance; X-ray structure; Synthesis; Isophthalamide; ACTIVE ANTIRETROVIRAL THERAPY; BETA-SECRETASE INHIBITORS; DRUG-RESISTANCE; POTENT; BACKBONE;

D O I：

10.1016/j.bmc.2017.04.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme K-i of 0.025 nM and antiviral IC50 of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 angstrom resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 angstrom resolution. These structures revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：5114 / 5127

页数：14

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