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

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• 作者：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
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：October 8, 2015
• 年：2015
• 卷：6
• 期：10
• 页码：1075-1079
• 全文大小：334K
• ISSN：1948-5875

文摘

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.