From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection

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.