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

doi:10.1021/acsmedchemlett.5b00254

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

Howard Hughes Medical Institution

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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 language	English (US)
Pages (from-to)	1075-1079
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	6
Issue number	10
DOIs	https://doi.org/10.1021/acsmedchemlett.5b00254
State	Published - Oct 8 2015

Keywords

HIV
mutations
non-nucleoside reverse transcriptase inhibitors
resistance
reverse transcriptase

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Access to Document

10.1021/acsmedchemlett.5b00254

Cite this

Gray, W. T., Frey, K. M., Laskey, S. B., Mislak, A. C., Spasov, K. A., Lee, W. G., Bollini, M., Siliciano, R. F., Jorgensen, W. L., & Anderson, K. S. (2015). Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance. ACS Medicinal Chemistry Letters, 6(10), 1075-1079. https://doi.org/10.1021/acsmedchemlett.5b00254

@article{0624f1ba04204d3885e1ab838ed8a22c,

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

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",

author = "Gray, {William T.} and Frey, {Kathleen M.} and Laskey, {Sarah B.} and Mislak, {Andrea C.} and Spasov, {Krasimir A.} and Lee, {Won Gil} and Mariela Bollini and Siliciano, {Robert F.} and Jorgensen, {William L.} and Anderson, {Karen S.}",

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

year = "2015",

month = oct,

day = "8",

doi = "10.1021/acsmedchemlett.5b00254",

language = "English (US)",

volume = "6",

pages = "1075--1079",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

number = "10",

}

TY - JOUR

T1 - Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance

AU - Gray, William T.

AU - Frey, Kathleen M.

AU - Laskey, Sarah B.

AU - Mislak, Andrea C.

AU - Spasov, Krasimir A.

AU - Lee, Won Gil

AU - Bollini, Mariela

AU - Siliciano, Robert F.

AU - Jorgensen, William L.

AU - Anderson, Karen S.

PY - 2015/10/8

Y1 - 2015/10/8

N2 - 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.

AB - 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.

KW - HIV

KW - mutations

KW - non-nucleoside reverse transcriptase inhibitors

KW - resistance

KW - reverse transcriptase

UR - http://www.scopus.com/inward/record.url?scp=84943746981&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943746981&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.5b00254

DO - 10.1021/acsmedchemlett.5b00254

M3 - Article

C2 - 26487915

AN - SCOPUS:84943746981

SN - 1948-5875

VL - 6

SP - 1075

EP - 1079

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 10

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this