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The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles

BACKGROUND: Bevirimat, the prototype Human Immunodeficiency Virus type 1 (HIV-1) maturation inhibitor, is highly potent in cell culture and efficacious in HIV-1 infected patients. In contrast to inhibitors that target the active site of the viral protease, bevirimat specifically inhibits a single cl...

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Autores principales: Nguyen, Albert T, Feasley, Christa L, Jackson, Ken W, Nitz, Theodore J, Salzwedel, Karl, Air, Gillian M, Sakalian, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267693/
https://www.ncbi.nlm.nih.gov/pubmed/22151792
http://dx.doi.org/10.1186/1742-4690-8-101
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author Nguyen, Albert T
Feasley, Christa L
Jackson, Ken W
Nitz, Theodore J
Salzwedel, Karl
Air, Gillian M
Sakalian, Michael
author_facet Nguyen, Albert T
Feasley, Christa L
Jackson, Ken W
Nitz, Theodore J
Salzwedel, Karl
Air, Gillian M
Sakalian, Michael
author_sort Nguyen, Albert T
collection PubMed
description BACKGROUND: Bevirimat, the prototype Human Immunodeficiency Virus type 1 (HIV-1) maturation inhibitor, is highly potent in cell culture and efficacious in HIV-1 infected patients. In contrast to inhibitors that target the active site of the viral protease, bevirimat specifically inhibits a single cleavage event, the final processing step for the Gag precursor where p25 (CA-SP1) is cleaved to p24 (CA) and SP1. RESULTS: In this study, photoaffinity analogs of bevirimat and mass spectrometry were employed to map the binding site of bevirimat to Gag within immature virus-like particles. Bevirimat analogs were found to crosslink to sequences overlapping, or proximal to, the CA-SP1 cleavage site, consistent with previous biochemical data on the effect of bevirimat on Gag processing and with genetic data from resistance mutations, in a region predicted by NMR and mutational studies to have α-helical character. Unexpectedly, a second region of interaction was found within the Major Homology Region (MHR). Extensive prior genetic evidence suggests that the MHR is critical for virus assembly. CONCLUSIONS: This is the first demonstration of a direct interaction between the maturation inhibitor, bevirimat, and its target, Gag. Information gained from this study sheds light on the mechanisms by which the virus develops resistance to this class of drug and may aid in the design of next-generation maturation inhibitors.
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spelling pubmed-32676932012-01-28 The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles Nguyen, Albert T Feasley, Christa L Jackson, Ken W Nitz, Theodore J Salzwedel, Karl Air, Gillian M Sakalian, Michael Retrovirology Research BACKGROUND: Bevirimat, the prototype Human Immunodeficiency Virus type 1 (HIV-1) maturation inhibitor, is highly potent in cell culture and efficacious in HIV-1 infected patients. In contrast to inhibitors that target the active site of the viral protease, bevirimat specifically inhibits a single cleavage event, the final processing step for the Gag precursor where p25 (CA-SP1) is cleaved to p24 (CA) and SP1. RESULTS: In this study, photoaffinity analogs of bevirimat and mass spectrometry were employed to map the binding site of bevirimat to Gag within immature virus-like particles. Bevirimat analogs were found to crosslink to sequences overlapping, or proximal to, the CA-SP1 cleavage site, consistent with previous biochemical data on the effect of bevirimat on Gag processing and with genetic data from resistance mutations, in a region predicted by NMR and mutational studies to have α-helical character. Unexpectedly, a second region of interaction was found within the Major Homology Region (MHR). Extensive prior genetic evidence suggests that the MHR is critical for virus assembly. CONCLUSIONS: This is the first demonstration of a direct interaction between the maturation inhibitor, bevirimat, and its target, Gag. Information gained from this study sheds light on the mechanisms by which the virus develops resistance to this class of drug and may aid in the design of next-generation maturation inhibitors. BioMed Central 2011-12-07 /pmc/articles/PMC3267693/ /pubmed/22151792 http://dx.doi.org/10.1186/1742-4690-8-101 Text en Copyright ©2011 Nguyen 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
Nguyen, Albert T
Feasley, Christa L
Jackson, Ken W
Nitz, Theodore J
Salzwedel, Karl
Air, Gillian M
Sakalian, Michael
The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles
title The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles
title_full The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles
title_fullStr The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles
title_full_unstemmed The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles
title_short The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles
title_sort prototype hiv-1 maturation inhibitor, bevirimat, binds to the ca-sp1 cleavage site in immature gag particles
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267693/
https://www.ncbi.nlm.nih.gov/pubmed/22151792
http://dx.doi.org/10.1186/1742-4690-8-101
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