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

ACS Med Chem Lett. 2015 Aug 31;6(10):1075-9. doi: 10.1021/acsmedchemlett.5b00254.

William T Gray ¹, Kathleen M Frey ¹, Sarah B Laskey ², Andrea C Mislak ¹, Krasimir A Spasov ¹, Won-Gil Lee ³, Mariela Bollini ³, Robert F Siliciano ⁴, William L Jorgensen ³, Karen S Anderson ¹

Affiliations

1 Department of Pharmacology, Yale University School of Medicine , New Haven, Connecticut 06520-8066, United States.
2 Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
3 Department of Chemistry, Yale University , New Haven, Connecticut 06530-8107, United States.
4 Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States ; Howard Hughes Medical Institute , Baltimore, Maryland 21205, United States.

PMID: 26487915 DOI: 10.1021/acsmedchemlett.5b00254

Abstract

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.

Keywords

HIV; mutations; non-nucleoside reverse transcriptase inhibitors; resistance; reverse transcriptase.

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