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

• DOI: 10.1073/pnas.1717932115
• Publication Date: 2017-12-26T17:42:27Z
• Authors: Shalley N. Kudalkar; Jagadish Beloor; Elias Quijano; Krasimir A. Spasov; Won-Gil Lee; José A. Cisneros; W. Mark Saltzman; Priti Kumar; William L. Jorgensen; Karen S. Anderson
• Keywords: Drug candidate

Significance Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy; however, concerns about poor pharmacological properties, dose restriction because toxicity, and drug resistance have limited treatment options. Our computational structure-guided design studies for lead optimization transformed a 5 µM virtual screening hit into class NNRTIs with remarkable potency, safety, profile, properties. We report representative, compound I, marked synergy existing HIV-1 drugs antiviral efficacy in HIV-1–infected humanized mice. A single long-acting nanoformulation I retains sustained levels ∼3 weeks, confirming potential as late-stage preclinical candidate. Additionally, these properties suggest that it may be promising candidate to evaluate preexposure prophylaxis.