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A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants

BACKGROUND: The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-character...

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Autores principales: Johnson, Barry C, Pauly, Gary T, Rai, Ganesha, Patel, Disha, Bauman, Joseph D, Baker, Heather L, Das, Kalyan, Schneider, Joel P, Maloney, David J, Arnold, Eddy, Thomas, Craig J, Hughes, Stephen H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549755/
https://www.ncbi.nlm.nih.gov/pubmed/23217210
http://dx.doi.org/10.1186/1742-4690-9-99
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author Johnson, Barry C
Pauly, Gary T
Rai, Ganesha
Patel, Disha
Bauman, Joseph D
Baker, Heather L
Das, Kalyan
Schneider, Joel P
Maloney, David J
Arnold, Eddy
Thomas, Craig J
Hughes, Stephen H
author_facet Johnson, Barry C
Pauly, Gary T
Rai, Ganesha
Patel, Disha
Bauman, Joseph D
Baker, Heather L
Das, Kalyan
Schneider, Joel P
Maloney, David J
Arnold, Eddy
Thomas, Craig J
Hughes, Stephen H
author_sort Johnson, Barry C
collection PubMed
description BACKGROUND: The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues of rilpivirine are described in the patent literature, but detailed analyses of their antiviral activities have not been published. This work addresses the ability of several of these analogues to inhibit the replication of wild-type (WT) and drug-resistant HIV-1. RESULTS: We used a combination of structure activity relationships and X-ray crystallography to examine NNRTIs that are structurally related to rilpivirine to determine their ability to inhibit WT RT and several clinically relevant RT mutants. Several analogues showed broad activity with only modest losses of potency when challenged with drug-resistant viruses. Structural analyses (crystallography or modeling) of several analogues whose potencies were reduced by RT mutations provide insight into why these compounds were less effective. CONCLUSIONS: Subtle variations between compounds can lead to profound differences in their activities and resistance profiles. Compounds with larger substitutions replacing the pyrimidine and benzonitrile groups of rilpivirine, which reorient pocket residues, tend to lose more activity against the mutants we tested. These results provide a deeper understanding of how rilpivirine and related compounds interact with the NNRTI binding pocket and should facilitate development of novel inhibitors.
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spelling pubmed-35497552013-01-23 A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants Johnson, Barry C Pauly, Gary T Rai, Ganesha Patel, Disha Bauman, Joseph D Baker, Heather L Das, Kalyan Schneider, Joel P Maloney, David J Arnold, Eddy Thomas, Craig J Hughes, Stephen H Retrovirology Research BACKGROUND: The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues of rilpivirine are described in the patent literature, but detailed analyses of their antiviral activities have not been published. This work addresses the ability of several of these analogues to inhibit the replication of wild-type (WT) and drug-resistant HIV-1. RESULTS: We used a combination of structure activity relationships and X-ray crystallography to examine NNRTIs that are structurally related to rilpivirine to determine their ability to inhibit WT RT and several clinically relevant RT mutants. Several analogues showed broad activity with only modest losses of potency when challenged with drug-resistant viruses. Structural analyses (crystallography or modeling) of several analogues whose potencies were reduced by RT mutations provide insight into why these compounds were less effective. CONCLUSIONS: Subtle variations between compounds can lead to profound differences in their activities and resistance profiles. Compounds with larger substitutions replacing the pyrimidine and benzonitrile groups of rilpivirine, which reorient pocket residues, tend to lose more activity against the mutants we tested. These results provide a deeper understanding of how rilpivirine and related compounds interact with the NNRTI binding pocket and should facilitate development of novel inhibitors. BioMed Central 2012-12-05 /pmc/articles/PMC3549755/ /pubmed/23217210 http://dx.doi.org/10.1186/1742-4690-9-99 Text en Copyright ©2012 Johnson et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Johnson, Barry C
Pauly, Gary T
Rai, Ganesha
Patel, Disha
Bauman, Joseph D
Baker, Heather L
Das, Kalyan
Schneider, Joel P
Maloney, David J
Arnold, Eddy
Thomas, Craig J
Hughes, Stephen H
A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants
title A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants
title_full A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants
title_fullStr A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants
title_full_unstemmed A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants
title_short A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants
title_sort comparison of the ability of rilpivirine (tmc278) and selected analogues to inhibit clinically relevant hiv-1 reverse transcriptase mutants
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549755/
https://www.ncbi.nlm.nih.gov/pubmed/23217210
http://dx.doi.org/10.1186/1742-4690-9-99
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