The parent grant supports our work on understanding the mechanism and inhibition of the viral polymerase, HIV reverse transcriptase. The HIV-1 (Human Immunodeficiency Virus) is a member of the retroviral family which is the major etiological agent involved in the development of acquired immunodeficiency syndrome (AIDS). The World Health Organization now estimates that in 2016 over 40 million people worldwide are infected. There are a number of potential targets in the HIV life cycle including HIV reverse transcriptase (RT), HIV protease, and more recently viral entry, attachment, and integration. Drugs targeting RT remain a cornerstone of AIDS therapy in most therapeutic regimens. The drugs that target HIV-1 RT are divided into two classes: nucleoside inhibitors (NRTIs) and non-nucleoside inhibitors (NNRTIs). Rapid development of drug resistance by the error prone RT, side effects, and issues of viral vs host polymerase selectivity necessitate the discovery of more effective NRTIs and NNRTIs with improved safety, pharmacological, and drug resistance profiles. Building on the discovery of a potent novel lead compound, using computationally and structure- guided design, the PI and collaborators used lead optimization to develop new NNRTIs have excellent potency on WT and drug resistant strains of HIV, optimal pharmacological properties, and synergy with clinically relevant NRTIs. This request is for supplemental funds to contribute toward purchase of a Waters Synapt G2 HDX system that will significantly enhance our structure-based drug design efforts. The requested instrument will also allow significant advances in other NIGMS-funded grants whose PIs are submitting cross-referenced Administrative Supplement applications: Titus Boggon and Benjamin Turk (MPI: R01-GM102262), Mark Lemmon (R35-GM122485), and Ya Ha (R01-GM112778), supported with funds from the Yale Cancer Biology Institute.
The World Health Organization estimates that in 2016 almost 40 million people worldwide are infected with HIV. There continues to be a significant need for new drugs and drug combinations to combat this disease. A great deal of effort to develop drugs against HIV has centered around the molecular target, HIV reverse transcriptase (RT). The studies outlined in this proposal will combine mechanistic studies with computational and structural guidance to design more effective therapies that have improved therapeutic properties.
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