The Effects of Side-Chain Configurations of a Retro–Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease |
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| Authors: | Chiyuki Awahara Daiki Oku Saki Furuta Kazuya Kobayashi Kenta Teruya Kenichi Akaji Yasunao Hattori |
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| Affiliation: | 1.Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan; (C.A.); (D.O.); (S.F.); (K.K.);2.Department of Neurochemistry, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8575, Japan;3.Center for Instrumental Analysis, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan |
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| Abstract: | 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. |
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| Keywords: | HTLV-1 protease, inhibitor, retro– inverso conversion, hydroxyethylamine isostere |
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