Structure-Based Discovery and Characterization of a Preclinical Drug Candidate for the Treatment of HIV-1 Infection

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2022 Nov 11

PMID 36366488

Authors

Dongwei Kang

Jinxuan Yang

Lingjin Kong

Ronghua Luo

Xusheng Huang

Tao Zhang

Mengdi Ma

Da Feng

Zhao Wang

Hao Fang

Peng Zhan

Yongtang Zheng

Xinyong Liu

Affiliations

Soon will be listed here.

Abstract

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) area key component of the current HIV-1 combination drug regimens. Although they exhibit potent anti-HIV-1 activity and modest toxicity, the emergence of mutant strains limits their application in clinical. Our previous research efforts contributed to the identification of compound K-5a2, which exhibits nanomolar activity in HIV-1-infected MT-4 cells. In this study, K-5a2 was shown to have a high level of anti-HIV-1 activity against various lab-adapted strains and clinical isolate strains, being comparable to ETR. Moreover, we showed the feasibility of K-5a2 as a preclinical anti-HIV-1 candidate by establishing its synergistic or additive anti-HIV-1 activity in combination with other representative anti-HIV-1 drugs and candidates. In addition, K-5a2 exhibited no inhibitory activity to the primary CYP isoforms and favorable pharmacokinetics. Taken together, its robust anti-HIV-1 potency, synergistic or additive effects with other anti-HIV drugs, and favorable pharmacokinetic and safety profiles make K-5a2 a potent alternative drug for HIV/AIDS treatment.

Citing Articles

Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study.

Zhou Z, Meng B, An J, Zhao F, Sun Y, Zeng D Int J Mol Sci. 2023; 24(2).

PMID: 36674730 PMC: 9865928. DOI: 10.3390/ijms24021215.

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