Drug Repurposing Screening for HIV and Other Viruses

National Center For Advancing Translational Sciences

Investigators

Abstract

HIV Latency-Reversing Agent Screening. Human immunodeficiency virus (HIV) has caused more than 35 million deaths worldwide. Management of the disease requires the daily administration of a combination of antiretroviral (ART) drugs for the life of the infected individual. This is due to the presence of an intact and inducible latent reservoir of HIV that rebounds after discontinuation of ART therapy. Elimination of this latent reservoir is a critical endpoint to eradicate HIV. ‘Shock and kill’ strategies are based on the reactivation of latent HIV with a Latency-Reversing Agent (LRA) with the consequent killing of the reactivated cell by either virus-induced and/or immune-mediated cell death. A screen of 10,000 small molecule compounds was carried out using a cell-based assay for LRAs acting through the STAT5 activation pathway. We have identified 20 confirmed and non-cytotoxic hits, which are being studied further. Lonafarnib As a Potential Drug Repurposing Candidate for SARS-CoV-2. Lonafarnib, an FDA-approved farnesyltransferase (FTase) inhibitor, was identified in a drug repurposing screen as a potent antiviral agent against SARS-CoV-2. In collaboration with Dr Liang’s lab at NIDDK, the study found that Lonafarnib effectively inhibited SARS-CoV-2 infection and showed synergy with approved antivirals remdesivir (RDV) and nirmatrelvir (NRTV). It was effective against multiple SARS-CoV-2 variants, including Alpha, Beta, Delta, and Omicron. Mechanistic studies indicated that Lonafarnib acts on multiple stages of the viral life cycle, including viral entry and replication. In vivo, Lonafarnib treatment in SARS-CoV-2-infected humanized mice resulted in a significant reduction in viral titers, improved pulmonary pathology, and better clinical outcomes. The study concludes that Lonafarnib, with its established safety profile, holds promise as a repurposed drug (Khan M et al. 2025. JCI Insight 10: e182704. PMID: 39625789).