Evaluation of Darunavir-derived HIV-1 Protease Inhibitors Incorporating P2' Amide-derivatives: Synthesis, Biological Evaluation and Structural Studies

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2023 Feb 4

PMID 36738797

Authors

Arun K Ghosh

Dana Shahabi

Maya Kipfmiller

Ajay K Ghosh

Megan Johnson

Yuan-Fang Wang

Johnson Agniswamy

Masayuki Amano

Irene T Weber

Hiroaki Mitsuya

Affiliations

Soon will be listed here.

Abstract

We report here the synthesis and biological evaluation of darunavir derived HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. The P2' 4-amino functionality was modified to make a number of amide derivatives to interact with residues in the S2' subsite of the HIV-1 protease active site. Several compounds exhibited picomolar enzyme inhibitory and low nanomolar antiviral activity. The X-ray crystal structure of the chloroacetate derivative bound to HIV-1 protease was determined. Interestingly, the active chloroacetate group converted to the acetate functionality during X-ray exposure. The structure revealed that the P2' carboxamide functionality makes enhanced hydrogen bonding interactions with the backbone atoms in the S2'-subsite.

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