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.
Department of Pharmacology, Yale University School of Medicine , New Haven, Connecticut 06520-8066, United States.
William T
WT
Gray
Department of Pharmacology, Yale University School of Medicine , New Haven, Connecticut 06520-8066, United States.
Kathleen M
KM
Frey
Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
Sarah B
SB
Laskey
Department of Pharmacology, Yale University School of Medicine , New Haven, Connecticut 06520-8066, United States.
Andrea C
AC
Mislak
Department of Pharmacology, Yale University School of Medicine , New Haven, Connecticut 06520-8066, United States.
Krasimir A
KA
Spasov
Department of Chemistry, Yale University , New Haven, Connecticut 06530-8107, United States.
Won-Gil
WG
Lee
Department of Chemistry, Yale University , New Haven, Connecticut 06530-8107, United States.
Mariela
M
Bollini
Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States ; Howard Hughes Medical Institute , Baltimore, Maryland 21205, United States.
Robert F
RF
Siliciano
Department of Chemistry, Yale University , New Haven, Connecticut 06530-8107, United States.
William L
WL
Jorgensen
Department of Pharmacology, Yale University School of Medicine , New Haven, Connecticut 06520-8066, United States.
Karen S
KS
Anderson
HIV; mutations; non-nucleoside reverse transcriptase inhibitors; resistance; reverse transcriptase