Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance

Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine. Fil: Gray, William T.. University of Yale; Estados Unidos Fil: Frey, Kathleen M.. University of Yale; Estados Unidos Fil: Laskey, Sarah B.. University Johns Hopkins; Estados Unidos Fil: Mislak, Andrea C.. University of Yale; Estados Unidos Fil: Spasov, Krasimir A.. University of Yale; Estados Unidos Fil: Lee, Won Gil. University of Yale; Estados Unidos Fil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Yale; Estados Unidos Fil: Siliciano, Robert F.. University Johns Hopkins; Estados Unidos. Howard Hughes Medial Institute; Estados Unidos Fil: Jorgensen, William L.. University of Yale; Estados Unidos Fil: Anderson, Karen S.. University of Yale; Estados Unidos