Structure-Based Discovery and Characterization of a Preclinical Drug Candidate for the Treatment of HIV-1 Infection.
Dongwei KangJinxuan YangLingjin KongRonghua LuoXusheng HuangTao ZhangMengdi MaDa FengZhao WangHao FangPeng ZhanYong-Tang ZhengXinyong LiuPublished in: Viruses (2022)
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.
Keyphrases
- antiretroviral therapy
- hiv infected
- hiv aids
- hiv positive
- human immunodeficiency virus
- hiv testing
- hepatitis c virus
- men who have sex with men
- escherichia coli
- south africa
- induced apoptosis
- oxidative stress
- small molecule
- drug delivery
- bone marrow
- cell proliferation
- smoking cessation
- cross sectional
- replacement therapy
- mesenchymal stem cells