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

Viruses. 2022 Oct 28;14(11):2390. doi: 10.3390/v14112390.

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.

Keywords: HIV-1; K-5a2; NNRTI; acute toxicity; pharmacodynamics; pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents* / therapeutic use
  • HIV Infections* / drug therapy
  • HIV Reverse Transcriptase
  • HIV-1*
  • Humans
  • Reverse Transcriptase Inhibitors / pharmacology

Substances

  • HIV Reverse Transcriptase
  • Reverse Transcriptase Inhibitors
  • Anti-HIV Agents

Grants and funding

We gratefully acknowledge financial support from the National Natural Science Foundation of China (NSFC Nos. 81903453, 81973181, 82060670), Shandong Provincial Natural Science Foundation (ZR2020YQ61, ZR2020JQ31, ZR2019BH011), National Key R&D Program of China (2021YFC2301703), Yunnan Key Research and Development Program (202103AC100005, 202103AQ100001), Qilu Young Scholars Program of Shandong University and Taishan Scholar Program at Shandong Province, and Project of Innovative Research Team of Yunnan Province (202005AE160005).