Picomolar inhibitors of HIV-1 reverse transcriptase: Design and crystallography of naphthyl phenyl ethers

Won Gil Lee; Kathleen M. Frey; Ricardo Gallardo-Macias; Krasimir A. Spasov; Mariela Bollini; Karen S. Anderson; William L. Jorgensen

doi:10.1021/ml5003713

Picomolar inhibitors of HIV-1 reverse transcriptase: Design and crystallography of naphthyl phenyl ethers

Won Gil Lee, Kathleen M. Frey, Ricardo Gallardo-Macias, Krasimir A. Spasov, Mariela Bollini, Karen S. Anderson, William L. Jorgensen

Institute for Therapeutics Discovery and Development

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Abstract

Catechol diethers that incorporate a 6-cyano-1-naphthyl substituent have been explored as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Promising compounds are reported that show midpicomolar activity against the wild-type virus and sub-20 nM activity against viral variants bearing Tyr181Cys and Lys103Asn mutations in HIV-RT. An X-ray crystal structure at 2.49 Å resolution is also reported for the key compound 6e with HIV-RT.

Original language	English (US)
Pages (from-to)	1259-1262
Number of pages	4
Journal	ACS Medicinal Chemistry Letters
Volume	5
Issue number	11
DOIs	https://doi.org/10.1021/ml5003713
State	Published - Nov 13 2014

Bibliographical note

Publisher Copyright:
© 2014 American Chemical Society.

Keywords

Anti-HIV agents
NNRTIs
protein crystallography

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title = "Picomolar inhibitors of HIV-1 reverse transcriptase: Design and crystallography of naphthyl phenyl ethers",

abstract = "Catechol diethers that incorporate a 6-cyano-1-naphthyl substituent have been explored as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Promising compounds are reported that show midpicomolar activity against the wild-type virus and sub-20 nM activity against viral variants bearing Tyr181Cys and Lys103Asn mutations in HIV-RT. An X-ray crystal structure at 2.49 {\AA} resolution is also reported for the key compound 6e with HIV-RT.",

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doi = "10.1021/ml5003713",

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AU - Lee, Won Gil

AU - Frey, Kathleen M.

AU - Gallardo-Macias, Ricardo

AU - Spasov, Krasimir A.

AU - Bollini, Mariela

AU - Anderson, Karen S.

AU - Jorgensen, William L.

PY - 2014/11/13

Y1 - 2014/11/13

N2 - Catechol diethers that incorporate a 6-cyano-1-naphthyl substituent have been explored as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Promising compounds are reported that show midpicomolar activity against the wild-type virus and sub-20 nM activity against viral variants bearing Tyr181Cys and Lys103Asn mutations in HIV-RT. An X-ray crystal structure at 2.49 Å resolution is also reported for the key compound 6e with HIV-RT.

AB - Catechol diethers that incorporate a 6-cyano-1-naphthyl substituent have been explored as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Promising compounds are reported that show midpicomolar activity against the wild-type virus and sub-20 nM activity against viral variants bearing Tyr181Cys and Lys103Asn mutations in HIV-RT. An X-ray crystal structure at 2.49 Å resolution is also reported for the key compound 6e with HIV-RT.

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KW - NNRTIs

KW - protein crystallography

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Picomolar inhibitors of HIV-1 reverse transcriptase: Design and crystallography of naphthyl phenyl ethers

Abstract

Bibliographical note

Keywords

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