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Asymmetric Deactivation of HIV-1 gp41 following Fusion Inhibitor Binding

Both equilibrium and nonequilibrium factors influence the efficacy of pharmaceutical agents that target intermediate states of biochemical reactions. We explored the intermediate state inhibition of gp41, part of the HIV-1 envelope glycoprotein complex (Env) that promotes viral entry through membran...

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Autores principales: Kahle, Kristen M., Steger, H. Kirby, Root, Michael J.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776349/
https://www.ncbi.nlm.nih.gov/pubmed/19956769
http://dx.doi.org/10.1371/journal.ppat.1000674
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author Kahle, Kristen M.
Steger, H. Kirby
Root, Michael J.
author_facet Kahle, Kristen M.
Steger, H. Kirby
Root, Michael J.
author_sort Kahle, Kristen M.
collection PubMed
description Both equilibrium and nonequilibrium factors influence the efficacy of pharmaceutical agents that target intermediate states of biochemical reactions. We explored the intermediate state inhibition of gp41, part of the HIV-1 envelope glycoprotein complex (Env) that promotes viral entry through membrane fusion. This process involves a series of gp41 conformational changes coordinated by Env interactions with cellular CD4 and a chemokine receptor. In a kinetic window between CD4 binding and membrane fusion, the N- and C-terminal regions of the gp41 ectodomain become transiently susceptible to inhibitors that disrupt Env structural transitions. In this study, we sought to identify kinetic parameters that influence the antiviral potency of two such gp41 inhibitors, C37 and 5-Helix. Employing a series of C37 and 5-Helix variants, we investigated the physical properties of gp41 inhibition, including the ability of inhibitor-bound gp41 to recover its fusion activity once inhibitor was removed from solution. Our results indicated that antiviral activity critically depended upon irreversible deactivation of inhibitor-bound gp41. For C37, which targets the N-terminal region of the gp41 ectodomain, deactivation was a slow process that depended on chemokine receptor binding to Env. For 5-Helix, which targets the C-terminal region of the gp41 ectodomain, deactivation occurred rapidly following inhibitor binding and was independent of chemokine receptor levels. Due to this kinetic disparity, C37 inhibition was largely reversible, while 5-Helix inhibition was functionally irreversible. The fundamental difference in deactivation mechanism points to an unappreciated asymmetry in gp41 following inhibitor binding and impacts the development of improved fusion inhibitors and HIV-1 vaccines. The results also demonstrate how the activities of intermediate state inhibitors critically depend upon the final disposition of inhibitor-bound states.
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spelling pubmed-27763492009-12-03 Asymmetric Deactivation of HIV-1 gp41 following Fusion Inhibitor Binding Kahle, Kristen M. Steger, H. Kirby Root, Michael J. PLoS Pathog Research Article Both equilibrium and nonequilibrium factors influence the efficacy of pharmaceutical agents that target intermediate states of biochemical reactions. We explored the intermediate state inhibition of gp41, part of the HIV-1 envelope glycoprotein complex (Env) that promotes viral entry through membrane fusion. This process involves a series of gp41 conformational changes coordinated by Env interactions with cellular CD4 and a chemokine receptor. In a kinetic window between CD4 binding and membrane fusion, the N- and C-terminal regions of the gp41 ectodomain become transiently susceptible to inhibitors that disrupt Env structural transitions. In this study, we sought to identify kinetic parameters that influence the antiviral potency of two such gp41 inhibitors, C37 and 5-Helix. Employing a series of C37 and 5-Helix variants, we investigated the physical properties of gp41 inhibition, including the ability of inhibitor-bound gp41 to recover its fusion activity once inhibitor was removed from solution. Our results indicated that antiviral activity critically depended upon irreversible deactivation of inhibitor-bound gp41. For C37, which targets the N-terminal region of the gp41 ectodomain, deactivation was a slow process that depended on chemokine receptor binding to Env. For 5-Helix, which targets the C-terminal region of the gp41 ectodomain, deactivation occurred rapidly following inhibitor binding and was independent of chemokine receptor levels. Due to this kinetic disparity, C37 inhibition was largely reversible, while 5-Helix inhibition was functionally irreversible. The fundamental difference in deactivation mechanism points to an unappreciated asymmetry in gp41 following inhibitor binding and impacts the development of improved fusion inhibitors and HIV-1 vaccines. The results also demonstrate how the activities of intermediate state inhibitors critically depend upon the final disposition of inhibitor-bound states. Public Library of Science 2009-11-26 /pmc/articles/PMC2776349/ /pubmed/19956769 http://dx.doi.org/10.1371/journal.ppat.1000674 Text en Kahle et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Kahle, Kristen M.
Steger, H. Kirby
Root, Michael J.
Asymmetric Deactivation of HIV-1 gp41 following Fusion Inhibitor Binding
title Asymmetric Deactivation of HIV-1 gp41 following Fusion Inhibitor Binding
title_full Asymmetric Deactivation of HIV-1 gp41 following Fusion Inhibitor Binding
title_fullStr Asymmetric Deactivation of HIV-1 gp41 following Fusion Inhibitor Binding
title_full_unstemmed Asymmetric Deactivation of HIV-1 gp41 following Fusion Inhibitor Binding
title_short Asymmetric Deactivation of HIV-1 gp41 following Fusion Inhibitor Binding
title_sort asymmetric deactivation of hiv-1 gp41 following fusion inhibitor binding
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776349/
https://www.ncbi.nlm.nih.gov/pubmed/19956769
http://dx.doi.org/10.1371/journal.ppat.1000674
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