Potent Inhibitors Active Against HIV Reverse Transcriptase with K101P, A Mutation Conferring Rilpivirine Resistance

WILLIAM T GRAY; KATHLEEN M. FREY,; SARAH B. LASKEY,; ANDREA C. MISLAK,; KRASIMIR A. SPASOV,; WON-GIL LEE,; MARIELA BOLLINI,; ROBERT F SILICIANO,; WILLIAM L JORGENSEN,; KAREN S. ANDERSON

acs medicinal chemistry letters

ACS

Año: 2015 p. 1 - 6

1948-5875

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 efavirenzand rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increasein the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a newcrystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for thecatechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.