The Effects of Side-Chain Configurations of a Retro–Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease

Chiyuki Awahara, Daiki Oku, Saki Furuta, Kazuya Kobayashi, Kenta Teruya, Kenichi Akaji, Yasunao Hattori

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

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 hydrox-yethylamine 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.

Original languageEnglish
Article number1646
JournalMolecules
Volume27
Issue number5
DOIs
Publication statusPublished - 2022 Mar 1

Keywords

  • HTLV-1 protease
  • Hydroxyethylamine isostere
  • Inhibitor
  • Retro–inverso conversion

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