Song M, Rajesh S, Hayashi Y, Kiso Y
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, 607-8412, Kyoto, Japan.
Bioorg Med Chem Lett. 2001 Sep 17;11(18):2465-8. doi: 10.1016/s0960-894x(01)00468-1.
To inhibit the HIV-1 protease dimerization necessary to exhibit enzymatic activity, we synthesized and evaluated a new beta-sheet peptide (compound 1), containing 4-(2-aminoethyl)-6-dibenzofuranpropionic acid as a conformationally restricted linker and a non-peptidic beta-strand mimetic, 2-[3-([2-[(9-fluorenylmethoxy)carbonyl]hydrazino]carbonyl)-4-methoxyanilino]-2-oxoacetic acid (Fmoc-Hao-OH, compound 2). Kinetic analysis showed that compound 1 inhibited the dimerization of HIV-1 protease by a dissociative mechanism with a K(id) value of 5.4 microM at 37 degrees C (pH 5.0). However, compound 2 showed a small shift in the slope of the lines in the Zhang-Poorman plot (K(id)=9.1 microM), suggesting that compound 2 inhibits the dimerization of HIV-1 PR not only through a dissociative mechanism but also through an active-site directed mechanism partly. This is the first study of a non-peptidic inhibitor of HIV-1 protease dimerization.
为抑制HIV-1蛋白酶展现酶活性所必需的二聚化，我们合成并评估了一种新的β-折叠肽（化合物1），其含有4-(2-氨基乙基)-6-二苯并呋喃丙酸作为构象受限的连接子以及一种非肽类β-链模拟物2-[3-([2-[(9-芴甲氧羰基)肼基]羰基]-4-甲氧基苯胺基]-2-氧代乙酸（Fmoc-Hao-OH，化合物2）。动力学分析表明，化合物1通过解离机制抑制HIV-1蛋白酶的二聚化，在37℃（pH 5.0）时K(id)值为5.4 μM。然而，化合物2在Zhang-Poorman图中直线斜率有小的变化（K(id)=9.1 μM），表明化合物2不仅通过解离机制而且部分通过活性位点导向机制抑制HIV-1 PR的二聚化。这是关于HIV-1蛋白酶二聚化的非肽类抑制剂的首次研究。
