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

Arun K Ghosh; Margherita Brindisi; Prasanth R Nyalapatla; Jun Takayama; Jean-Rene Ella-Menye; Sofiya Yashchuk; Johnson Agniswamy; Yuan-Fang Wang; Manabu Aoki; Masayuki Amano; Irene T Weber; Hiroaki Mitsuya

doi:10.1016/j.bmc.2017.04.005

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

Bioorg Med Chem. 2017 Oct 1;25(19):5114-5127. doi: 10.1016/j.bmc.2017.04.005. Epub 2017 Apr 9.

Affiliations

¹ Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA. Electronic address: akghosh@purdue.edu.
² Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.
³ Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
⁴ Department of Hematology, Kumamoto University of Medicine, Kumamoto 860-8556, Japan; Department of Infectious Diseases, Kumamoto University of Medicine, Kumamoto 860-8556, Japan.
⁵ Department of Biology, Georgia State University, Atlanta, GA 30303, USA; Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
⁶ Department of Hematology, Kumamoto University of Medicine, Kumamoto 860-8556, Japan; Department of Infectious Diseases, Kumamoto University of Medicine, Kumamoto 860-8556, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute, Bethesda, MD 20892, USA; Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, Shinjuku, Tokyo 162-8655, Japan.

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 K_i of 0.025nM and antiviral IC₅₀ of 69nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27Å resolution. These structures revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site.

Keywords: Drug-resistance; HIV-1 protease; Isophthalamide; Synthesis; X-ray structure.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amides / chemistry
Amides / pharmacology
Crystallography, X-Ray
Drug Design*
HIV Infections / drug therapy
HIV Infections / virology
HIV Protease / chemistry
HIV Protease / metabolism*
HIV Protease Inhibitors / chemistry*
HIV Protease Inhibitors / pharmacology*
HIV-1 / drug effects*
HIV-1 / enzymology
Humans
Molecular Docking Simulation
Phthalic Acids / chemistry*
Phthalic Acids / pharmacology*

Substances

Amides
HIV Protease Inhibitors
Phthalic Acids
HIV Protease
p16 protease, Human immunodeficiency virus 1

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding