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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1075-1079
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume6
Issue number10
DOIs
StatePublished - Oct 8 2015

Keywords

  • HIV
  • mutations
  • non-nucleoside reverse transcriptase inhibitors
  • resistance
  • reverse transcriptase

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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