Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

The clinical benefits of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are hindered by their unsatisfactory pharmacokinetic (PK) properties along with the rapid development of drug-resistant variants. However, the clinical efficacy of these inhibitors can be improved by developing compounds with enhanced pharmacological profiles and heightened antiviral activity. We used computational and structure-guided design to develop two next-generation NNRTI drug candidates, compounds I and II, which are members of a class of catechol diethers. We evaluated the preclinical potential of these compounds in BALB/c mice because of their high solubility (510 μg/mL for compound I and 82.9 μg/mL for compound II), low cytotoxicity and enhanced antiviral activity against wild type (WT) HIV-1 RT and resistant variants. Additionally, crystal structures of compounds I and II with WT RT suggested an optimal binding to the NNRTI binding pocket favoring the high anti-viral potency. A single intraperitoneal dose of compounds I and II exhibited a prolonged serum residence time of 48 h and concentration maximum (Cmax) of 4000-15 000 fold higher than their therapeutic / effective concentrations. These Cmaxs were 4-15 fold lower than their cytotoxic concentrations observed in MT-2 cells. Compound II showed enhanced AUC(0-last) and decreased plasma clearance over compound I and efavirenz, the standard of care NNRTI. Hence, the overall PK profile of compound II was excellent compared to that of compound I and efavirenz. Furthermore, both compounds were very well tolerated in BALB/c mice without any detectable acute toxicity. Taken together, these data suggest that compounds I and II possess improved anti-HIV-1 potency, remarkable in vivo safety and prolonged in vivo circulation time suggesting strong potential for further development as new NNRTIs for the potential treatment of HIV infection.