The Effects of Side-Chain Configurations of a Retro–Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease
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...
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MDPI AG
2022-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/5/1646 |
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| author | Chiyuki Awahara Daiki Oku Saki Furuta Kazuya Kobayashi Kenta Teruya Kenichi Akaji Yasunao Hattori |
| author_facet | Chiyuki Awahara Daiki Oku Saki Furuta Kazuya Kobayashi Kenta Teruya Kenichi Akaji Yasunao Hattori |
| author_sort | Chiyuki Awahara |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T20:29:11Z |
| format | Article |
| id | doaj.art-729c42ba1efe4d00ae669f19ffbe04f5 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T20:29:11Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-729c42ba1efe4d00ae669f19ffbe04f52023-11-23T23:27:39ZengMDPI AGMolecules1420-30492022-03-01275164610.3390/molecules27051646The Effects of Side-Chain Configurations of a Retro–Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 ProteaseChiyuki Awahara0Daiki Oku1Saki Furuta2Kazuya Kobayashi3Kenta Teruya4Kenichi Akaji5Yasunao Hattori6Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, JapanDepartment of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, JapanDepartment of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, JapanDepartment of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, JapanDepartment of Neurochemistry, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8575, JapanDepartment of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, JapanCenter for Instrumental Analysis, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, JapanIn 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.https://www.mdpi.com/1420-3049/27/5/1646HTLV-1 proteaseinhibitorretro–inverso conversionhydroxyethylamine isostere |
| spellingShingle | Chiyuki Awahara Daiki Oku Saki Furuta Kazuya Kobayashi Kenta Teruya Kenichi Akaji Yasunao Hattori The Effects of Side-Chain Configurations of a Retro–Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease Molecules HTLV-1 protease inhibitor retro–inverso conversion hydroxyethylamine isostere |
| title | The Effects of Side-Chain Configurations of a Retro–Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease |
| title_full | The Effects of Side-Chain Configurations of a Retro–Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease |
| title_fullStr | The Effects of Side-Chain Configurations of a Retro–Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease |
| title_full_unstemmed | The Effects of Side-Chain Configurations of a Retro–Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease |
| title_short | The Effects of Side-Chain Configurations of a Retro–Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease |
| title_sort | effects of side chain configurations of a retro inverso type inhibitor on the human t cell leukemia virus htlv 1 protease |
| topic | HTLV-1 protease inhibitor retro–inverso conversion hydroxyethylamine isostere |
| url | https://www.mdpi.com/1420-3049/27/5/1646 |
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