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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3904841?pdf=render |
| _version_ | 1818061199413084160 |
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| author | Young Do Kwon Judith M LaLonde Yongping Yang Mark A Elban Akihiro Sugawara Joel R Courter David M Jones Amos B Smith Asim K Debnath Peter D Kwong |
| author_facet | Young Do Kwon Judith M LaLonde Yongping Yang Mark A Elban Akihiro Sugawara Joel R Courter David M Jones Amos B Smith Asim K Debnath Peter D Kwong |
| author_sort | Young Do Kwon |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-10T13:44:31Z |
| format | Article |
| id | doaj.art-e73d4da82ce24696811bc79c63f7a780 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T13:44:31Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-e73d4da82ce24696811bc79c63f7a7802022-12-22T01:46:32ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0191e8594010.1371/journal.pone.0085940Crystal structures of HIV-1 gp120 envelope glycoprotein in complex with NBD analogues that target the CD4-binding site.Young Do KwonJudith M LaLondeYongping YangMark A ElbanAkihiro SugawaraJoel R CourterDavid M JonesAmos B SmithAsim K DebnathPeter D KwongEfforts 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.http://europepmc.org/articles/PMC3904841?pdf=render |
| spellingShingle | Young Do Kwon Judith M LaLonde Yongping Yang Mark A Elban Akihiro Sugawara Joel R Courter David M Jones Amos B Smith Asim K Debnath Peter D Kwong Crystal structures of HIV-1 gp120 envelope glycoprotein in complex with NBD analogues that target the CD4-binding site. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC3904841?pdf=render |
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