S. Kudalkar, J. Beloor, Elias Quijano
Dec 26, 2017
Proceedings of the National Academy of Sciences
Significance Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy; however, concerns about poor pharmacological properties, dose restriction because of toxicity, and drug resistance have limited treatment options. Our computational and structure-guided design studies for lead optimization have transformed a 5 µM virtual screening hit into a class of NNRTIs with remarkable potency, safety, drug resistance profile, and pharmacological properties. We report a representative, compound I, with marked synergy with existing HIV-1 drugs and antiviral efficacy in HIV-1–infected humanized mice. A single dose of long-acting nanoformulation of compound I retains sustained levels and efficacy for ∼3 weeks, confirming potential as a late-stage preclinical candidate. Additionally, these properties of compound I suggest that it may be a promising candidate to evaluate for preexposure prophylaxis. The HIV-1 pandemic affecting over 37 million people worldwide continues, with nearly one-half of the infected population on highly active antiretroviral therapy (HAART). Major therapeutic challenges remain because of the emergence of drug-resistant HIV-1 strains, limitations because of safety and toxicity with current HIV-1 drugs, and patient compliance for lifelong, daily treatment regimens. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) that target the viral polymerase have been a key component of the current HIV-1 combination drug regimens; however, these issues hamper them. Thus, the development of novel more effective NNRTIs as anti–HIV-1 agents with fewer long-term liabilities, efficacy on new drug-resistant HIV-1 strains, and less frequent dosing is crucial. Using a computational and structure-based design strategy to guide lead optimization, a 5 µM virtual screening hit was transformed to a series of very potent nanomolar to picomolar catechol diethers. One representative, compound I, was shown to have nanomolar activity in HIV-1–infected T cells, potency on clinically relevant HIV-1 drug-resistant strains, lack of cytotoxicity and off-target effects, and excellent in vivo pharmacokinetic behavior. In this report, we show the feasibility of compound I as a late-stage preclinical candidate by establishing synergistic antiviral activity with existing HIV-1 drugs and clinical candidates and efficacy in HIV-1–infected humanized [human peripheral blood lymphocyte (Hu-PBL)] mice by completely suppressing viral loads and preventing human CD4+ T-cell loss. Moreover, a long-acting nanoformulation of compound I [compound I nanoparticle (compound I-NP)] in poly(lactide-coglycolide) (PLGA) was developed that shows sustained maintenance of plasma drug concentrations and drug efficacy for almost 3 weeks after a single dose.