The human immunodeficiency virus (HIV) is a retrovirus. It can cause acquired immunodeficiency syndrome (AIDS), and weaken people’s defense against many infections and some types of cancer. This virus kills millions of people every year. Therefore, the treatment of AIDS is an important research topic in the world. The highly active antiretroviral therapy (HAART) has been used to treat HIV, which can extend the life expectancy of patients by more than 24 years. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important part of HAART. These inhibitors can inhibit reverse transcriptase by binding to NNRTI binding pocket (NNIBP). Thus, the development of NNRTIs has become a key focus of AIDS treatment.

ZLM-66, a Doravirine analogue, is an orally active NNRTIs which has highly inhibitory activity against HIV.

ZLM-66 inhibits wild type (WT) HIV-1 reverse transcriptase (RT) with an IC50 of 41 nM, as well as suppresses multiple HIV-1 mutant strains with EC50s of 13 nM, 13 nM, 24 nM, 25 nM and 58 nM against HIV-1 WT, K103N, L1001, E138K, and Y181C, respectively. Besides, it exhibits a very weak inhibitory effect on CYP isoforms, suggesting that ZLM-66 has no significant effect on drug-drug interactions. ZLM-66 has little inhibitory activity against hERG in CHO-hERG cells, with an IC50>200 μM. It is indicating that this agent may not be cardiotoxic.

Following the in vivo research, ZLM-66 (1 mg/kg for IV; 5 mg/kg for PO; single dosage) exhibits better pharmacokinetic properties than Doravirine. It has low clearance (CL=1072.31 mL/h/kg) and moderate half-life (T1/2=1.90 h) after IV administration; shows a longer half-life (T1/2=8.45 h), approximately twice that of Doravirine (T1/2=4.4 h), and impressive oral bioavailability of 140.24%. after PO administration. Taken together, ZLM-66 has the potential to become a orally active agent for HIV treatment.

In conclusion, ZLM-66 is a potent NNRTIs against HIV.


[1] Zhao LM, et al. Eur J Med Chem. 2022 Oct 5;240:114581.