降低对多药耐药HIV-1毒株具有纳摩尔效力的HIV蛋白酶抑制剂的肽特性。

Reduction of peptide character of HIV protease inhibitors that exhibit nanomolar potency against multidrug resistant HIV-1 strains.

作者信息

Tamamura Hirokazu, Koh Yasuhiro, Ueda Satoshi, Sasaki Yoshikazu, Yamasaki Tomonori, Aoki Manabu, Maeda Kenji, Watai Yoriko, Arikuni Hisashi, Otaka Akira, Mitsuya Hiroaki, Fujii Nobutaka

机构信息

Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.

出版信息

J Med Chem. 2003 Apr 24;46(9):1764-8. doi: 10.1021/jm020537i.

DOI:10.1021/jm020537i

PMID:12699395

Abstract

Novel HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere as a transition state-mimic king structure were synthesized by combining substructures of known HIV protease inhibitors. Among them, TYA5 and TYB5 were proven to be not only potent enzyme inhibitors (K(i) = 0.12 nM and 0.10 nM, respectively) but also strong anti-HIV agents (IC(50) = 9.5 nM and 66 nM, respectively), even against viral strains with multidrug resistance. Furthermore, insertion of an (E)-alkene dipeptide isostere at the P(1)-P(2) position of TYB5 led to development of a purely nonpeptidic protease inhibitor, TYB1 (K(i) = 0.38 nM, IC(50) = 160 nM).

摘要

通过组合已知HIV蛋白酶抑制剂的亚结构，合成了含有羟乙胺二肽电子等排体作为过渡态模拟结构的新型HIV蛋白酶抑制剂。其中，TYA5和TYB5不仅被证明是有效的酶抑制剂（K(i)分别为0.12 nM和0.10 nM），而且还是强效抗HIV药物（IC(50)分别为9.5 nM和66 nM），甚至对具有多药耐药性的病毒株也有效。此外，在TYB5的P(1)-P(2)位置插入(E)-烯烃二肽电子等排体导致了一种纯非肽类蛋白酶抑制剂TYB1的开发（K(i) = 0.38 nM，IC(50) = 160 nM）。