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Title: Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex

Abstract

Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme Ki of 0.025 nM and antiviral IC50 of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 Å resolution. These structures revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.

Authors:
; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1418041
Resource Type:
Journal Article
Resource Relation:
Journal Name: Bioorganic and Medicinal Chemistry; Journal Volume: 25; Journal Issue: 19
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Ghosh, Arun K., Brindisi, Margherita, Nyalapatla, Prasanth R., Takayama, Jun, Ella-Menye, Jean-Rene, Yashchuk, Sofiya, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Amano, Masayuki, Weber, Irene T., and Mitsuya, Hiroaki. Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex. United States: N. p., 2017. Web. doi:10.1016/j.bmc.2017.04.005.
Ghosh, Arun K., Brindisi, Margherita, Nyalapatla, Prasanth R., Takayama, Jun, Ella-Menye, Jean-Rene, Yashchuk, Sofiya, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Amano, Masayuki, Weber, Irene T., & Mitsuya, Hiroaki. Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex. United States. doi:10.1016/j.bmc.2017.04.005.
Ghosh, Arun K., Brindisi, Margherita, Nyalapatla, Prasanth R., Takayama, Jun, Ella-Menye, Jean-Rene, Yashchuk, Sofiya, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Amano, Masayuki, Weber, Irene T., and Mitsuya, Hiroaki. Sun . "Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex". United States. doi:10.1016/j.bmc.2017.04.005.
@article{osti_1418041,
title = {Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex},
author = {Ghosh, Arun K. and Brindisi, Margherita and Nyalapatla, Prasanth R. and Takayama, Jun and Ella-Menye, Jean-Rene and Yashchuk, Sofiya and Agniswamy, Johnson and Wang, Yuan-Fang and Aoki, Manabu and Amano, Masayuki and Weber, Irene T. and Mitsuya, Hiroaki},
abstractNote = {Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme Ki of 0.025 nM and antiviral IC50 of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 Å resolution. These structures revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.},
doi = {10.1016/j.bmc.2017.04.005},
journal = {Bioorganic and Medicinal Chemistry},
number = 19,
volume = 25,
place = {United States},
year = {Sun Oct 01 00:00:00 EDT 2017},
month = {Sun Oct 01 00:00:00 EDT 2017}
}