Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Department of Neurochemistry, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8575, Japan.
Molecules. 2022 Mar 2;27(5):1646. doi: 10.3390/molecules27051646.
In this study, the effects of side-chain configurations of D-Ile residues of a retro-inverso (RI)-type inhibitor on the human T-cell leukemia virus type 1 (HTLV-1) protease containing a hydroxyethylamine dipeptide isostere were clarified. Prior to evaluation using the RI-type inhibitor, the effects of side-chain configurations of Ile residues of the substrate peptide on the HTLV-1 protease were examined to estimate the influence of side-chain configurations on enzyme activity. Based on the estimation of the influence of side-chain configurations on protease affinity, the RI-type inhibitors containing a D-allo-Ile residue in the corresponding substrate sequence, instead of a D-Ile residue, were synthesized via 9-fluorenylmethoxycarbonyl-based solid-phase peptide synthesis. Refolded recombinant HTLV-1 protease (1-116, L40I) was used for the simple and short evaluation of the inhibitory activities of the synthesized RI-type inhibitors. The results clearly indicated that mimicking the whole topology, comprising both the main- and side-chain structures of the parent inhibitor, is effective for the design of potent RI-modified protease inhibitors.
在这项研究中，阐明了 D-Ile 残基侧链构型对包含羟乙基胺二肽拟肽的人 T 细胞白血病病毒 1 型（HTLV-1）蛋白酶的反式-内型（RI）抑制剂的影响。在使用 RI 型抑制剂进行评估之前，检查了底物肽中 Ile 残基的侧链构型对 HTLV-1 蛋白酶的影响，以估计侧链构型对酶活性的影响。基于对侧链构型对蛋白酶亲和力影响的估计，通过基于 9-芴甲氧羰基的固相肽合成，在相应的底物序列中用 D-allo-Ile 残基代替 D-Ile 残基合成了 RI 型抑制剂。使用复性的重组 HTLV-1 蛋白酶（1-116，L40I）进行合成的 RI 型抑制剂抑制活性的简单和短期评估。结果清楚地表明，模拟整个拓扑结构，包括母体抑制剂的主链和侧链结构，对于设计有效的 RI 修饰蛋白酶抑制剂是有效的。
