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) v...

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Bibliographic Details
Authors: Gray, William T., Frey, Kathleen M., Laskey, Sarah B., Mislak, Andrea C., Spasov, Krasimir A., Lee, Won Gil, Bollini, Mariela, Siliciano, Robert F., Jorgensen, William L., Anderson, Karen S.
Format: article
Status:Published version
Publication Date:2015
Country:Argentina
Institution:Consejo Nacional de Investigaciones Científicas y Técnicas
Repository:CONICET Digital (CONICET)
Language:English
OAI Identifier:oai:ri.conicet.gov.ar:11336/15923
Online Access:http://hdl.handle.net/11336/15923
Access Level:Open access
Keyword:HIV
Rreverse transcriptase
Non-nucleoside reverse transcriptase inhibitors
Resistance
Mutations
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
Description
Summary: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.

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