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Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site
Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, a...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904841/ https://www.ncbi.nlm.nih.gov/pubmed/24489681 http://dx.doi.org/10.1371/journal.pone.0085940 |
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author | Kwon, Young Do LaLonde, Judith M. Yang, Yongping Elban, Mark A. Sugawara, Akihiro Courter, Joel R. Jones, David M. Smith, Amos B. Debnath, Asim K. Kwong, Peter D. |
author_facet | Kwon, Young Do LaLonde, Judith M. Yang, Yongping Elban, Mark A. Sugawara, Akihiro Courter, Joel R. Jones, David M. Smith, Amos B. Debnath, Asim K. Kwong, Peter D. |
author_sort | Kwon, Young Do |
collection | PubMed |
description | Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization. |
format | Online Article Text |
id | pubmed-3904841 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39048412014-01-31 Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site Kwon, Young Do LaLonde, Judith M. Yang, Yongping Elban, Mark A. Sugawara, Akihiro Courter, Joel R. Jones, David M. Smith, Amos B. Debnath, Asim K. Kwong, Peter D. PLoS One Research Article Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization. Public Library of Science 2014-01-28 /pmc/articles/PMC3904841/ /pubmed/24489681 http://dx.doi.org/10.1371/journal.pone.0085940 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Kwon, Young Do LaLonde, Judith M. Yang, Yongping Elban, Mark A. Sugawara, Akihiro Courter, Joel R. Jones, David M. Smith, Amos B. Debnath, Asim K. Kwong, Peter D. Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site |
title | Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site |
title_full | Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site |
title_fullStr | Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site |
title_full_unstemmed | Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site |
title_short | Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site |
title_sort | crystal structures of hiv-1 gp120 envelope glycoprotein in complex with nbd analogues that target the cd4-binding site |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904841/ https://www.ncbi.nlm.nih.gov/pubmed/24489681 http://dx.doi.org/10.1371/journal.pone.0085940 |
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