TY - JOUR
T1 - The Effects of Side-Chain Configurations of a Retro–Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease
AU - Awahara, Chiyuki
AU - Oku, Daiki
AU - Furuta, Saki
AU - Kobayashi, Kazuya
AU - Teruya, Kenta
AU - Akaji, Kenichi
AU - Hattori, Yasunao
N1 - Funding Information:
Funding: This research was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant No. 21590017 to K.A.).
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
KW - HTLV-1 protease
KW - Hydroxyethylamine isostere
KW - Inhibitor
KW - Retro–inverso conversion
UR - http://www.scopus.com/inward/record.url?scp=85126049665&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85126049665&partnerID=8YFLogxK
U2 - 10.3390/molecules27051646
DO - 10.3390/molecules27051646
M3 - Article
C2 - 35268749
AN - SCOPUS:85126049665
SN - 1420-3049
VL - 27
JO - Molecules
JF - Molecules
IS - 5
M1 - 1646
ER -