HIV-1蛋白酶抑制剂：糖肽模拟物的合成与生物学评价

HIV-1 protease inhibitors: synthesis and biological evaluation of glycopeptidemimetics.

作者信息

Ghosh A K, McKee S P, Sanders W M, Darke P L, Zugay J A, Emini E A, Schleif W A, Quintero J C, Huff J R, Anderson P S

机构信息

Department of Medicinal Chemistry, Molecular Biology, Merck Research Laboratories, West Point, Pennsylvania 19486.

出版信息

Drug Des Discov. 1993;10(1):77-88.

PMID:8399995

Abstract

A series of glycopeptidemimetics based on the hydroxyethylene Phe-Phe isostere have been synthesized and evaluated for their ability to inhibit the enzyme HIV-1 protease. Incorporation of carbohydrate moieties at the P'2-position and elimination of P'3 amino acid in our lead compound 1, provided inhibitors with only nanomolar potencies (400-800 nM). However, incorporation of a carbohydrate moiety at the P'3-position with branched chain amino acid at the P'2-position, resulted in inhibitors with subnanomolar potencies. Within this series, compound 21 was the most potent inhibitor (IC50 value 0.17 nM). This compound has also shown to block the spread of HIV-1 in T-lymphoid cells at an inhibitor concentration of 200 nM.

摘要

基于羟乙烯基苯丙氨酸-苯丙氨酸等排体合成了一系列糖肽模拟物，并对其抑制HIV-1蛋白酶的能力进行了评估。在先导化合物1的P'2位引入碳水化合物部分并去除P'3氨基酸，得到了仅具有纳摩尔效力（400-800 nM）的抑制剂。然而，在P'3位引入碳水化合物部分并在P'2位引入支链氨基酸，得到了具有亚纳摩尔效力的抑制剂。在该系列中，化合物21是最有效的抑制剂（IC50值为0.17 nM）。该化合物在200 nM的抑制剂浓度下也显示出能阻断HIV-1在T淋巴细胞中的传播。