National Institute of Allergy and Infectious Diseases 5R37AI155072-34

Mechanism and Inhibition of HIV Reverse Transcriptase

This award funds research at Yale University to develop new and improved non-nucleoside inhibitors of HIV reverse transcriptase to combat drug-resistant HIV strains and improve treatment safety and efficacy, including novel mechanisms to target HIV reservoirs.

Description

The HIV-1 (Human Immunodeficiency Virus) is a member of the retroviral family which contains a single-stranded RNA genome and is the major etiological agent involved in the development of acquired immunodeficiency syndrome or AIDS. The WHO now estimates that in 2022 over 40 million people worldwide are infected. Development of antiretroviral therapy (ART) provided much progress over the past several decades. Continual emergence of drug resistance HIV variants and side effects of life-long therapy necessitate the development of new agents and long-acting therapies to increase patient compliance. Developing PrEP prophylactic and combination therapies would be highly beneficial as well as new approaches to reduce HIV reservoirs. Successful drug targets include HIV reverse transcriptase (RT), HIV protease, integration, viral entry, attachment, and capsid. Drugs targeting RT remain a cornerstone of AIDS therapy and are divided into two classes: nucleoside inhibitors (NRTIs) and non-nucleoside inhibitors (NNRTIs). NNRTIs with improved safety, pharmacological, drug resistance profiles, and dosing regimens are still needed. Building on the discovery of potent novel lead compounds, using computational and structure-guided design, the PI and collaborators have developed several new classes of NNRTIs with excellent potency on WT and drug-resistant strains, optimal pharmacological properties, and efficacy in AIDS mouse models, including long-acting and extended-release formulations. Some NNRTIs work via a different mechanism involving Gag-Pol dimerization, premature HIV protease activation, and inflammasome cell-killing of HIV-1 infected cells via pyroptosis. Studies aim to develop this new class as a strategy to attack HIV reservoirs.

View original record