Rational Design of Potent Non-Nucleoside Inhibitors of HIV‑1 Reverse Transcriptase
A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse t...
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| Veröffentlicht in: | J. Med. Chem 2012-12, Vol.55 (23), p.10601-10609 |
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| container_end_page | 10609 |
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| container_issue | 23 |
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| container_title | J. Med. Chem |
| container_volume | 55 |
| creator | Chong, Pek Sebahar, Paul Youngman, Michael Garrido, Dulce Zhang, Huichang Stewart, Eugene L. Nolte, Robert T. Wang, Liping Ferris, Robert G. Edelstein, Mark Weaver, Kurt Mathis, Amanda Peat, Andrew |
| description | A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50 < 1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species. |
| doi_str_mv | 10.1021/jm301294g |
| format | Article |
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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50 < 1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm301294g</identifier><identifier>PMID: 23137340</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Crystallography, X-Ray ; Drug Design ; HIV Reverse Transcriptase - antagonists & inhibitors ; HIV-1 - drug effects ; Microbial Sensitivity Tests ; Models, Molecular ; Reverse Transcriptase Inhibitors - chemistry ; Reverse Transcriptase Inhibitors - pharmacology</subject><ispartof>J. Med. 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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Rational Design of Potent Non-Nucleoside Inhibitors of HIV‑1 Reverse Transcriptase</title><title>J. Med. Chem</title><addtitle>J. Med. Chem</addtitle><description>A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50 < 1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.</description><subject>Crystallography, X-Ray</subject><subject>Drug Design</subject><subject>HIV Reverse Transcriptase - antagonists & inhibitors</subject><subject>HIV-1 - drug effects</subject><subject>Microbial Sensitivity Tests</subject><subject>Models, Molecular</subject><subject>Reverse Transcriptase Inhibitors - chemistry</subject><subject>Reverse Transcriptase Inhibitors - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0M1KAzEUhuEgitbqwhuQQRB0MXqSzLQzS_G3ICpS3Q6Z9IymTJOakxHceQveoldiSqsrV4Hw8HF4GdvjcMJB8NPpTAIXZfayxno8F5BmBWTrrAcgRCoGQm6xbaIpAEgu5CbbEpLLocygx8aPKhhnVZtcIJkXm7gmeXABbUjunE3vOt2iIzPBZGRfTW2C87QwN6Pn788vnjziO3rCZOyVJe3NPCjCHbbRqJZwd_X22dPV5fj8Jr29vx6dn92mKoMipLqRhYK8LlBCA6qWdVNnBQo-wWEG0BR11iCX-SQf8EINFidDqfP4McRyyLnss4PlrqNgKtImoH7VzlrUoeJQytghoqMlmnv31iGFamZIY9sqi66jKhYpIS-jjvR4SbV3RB6bau7NTPmPOFYtSld_paPdX8129Qwnf_I3bQSHS6A0VVPX-RiZ_hn6ATmcg8s</recordid><startdate>20121213</startdate><enddate>20121213</enddate><creator>Chong, Pek</creator><creator>Sebahar, Paul</creator><creator>Youngman, Michael</creator><creator>Garrido, Dulce</creator><creator>Zhang, Huichang</creator><creator>Stewart, Eugene L.</creator><creator>Nolte, Robert T.</creator><creator>Wang, Liping</creator><creator>Ferris, Robert G.</creator><creator>Edelstein, Mark</creator><creator>Weaver, Kurt</creator><creator>Mathis, Amanda</creator><creator>Peat, Andrew</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>20121213</creationdate><title>Rational Design of Potent Non-Nucleoside Inhibitors of HIV‑1 Reverse Transcriptase</title><author>Chong, Pek ; Sebahar, Paul ; Youngman, Michael ; Garrido, Dulce ; Zhang, Huichang ; Stewart, Eugene L. ; Nolte, Robert T. ; Wang, Liping ; Ferris, Robert G. ; Edelstein, Mark ; Weaver, Kurt ; Mathis, Amanda ; Peat, Andrew</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a408t-cf38a05b8e30f0ab3bfb48e21de7400f8b4fe135d5618a6137309c535d7e97113</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Crystallography, X-Ray</topic><topic>Drug Design</topic><topic>HIV Reverse Transcriptase - antagonists & inhibitors</topic><topic>HIV-1 - drug effects</topic><topic>Microbial Sensitivity Tests</topic><topic>Models, Molecular</topic><topic>Reverse Transcriptase Inhibitors - chemistry</topic><topic>Reverse Transcriptase Inhibitors - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chong, Pek</creatorcontrib><creatorcontrib>Sebahar, Paul</creatorcontrib><creatorcontrib>Youngman, Michael</creatorcontrib><creatorcontrib>Garrido, Dulce</creatorcontrib><creatorcontrib>Zhang, Huichang</creatorcontrib><creatorcontrib>Stewart, Eugene L.</creatorcontrib><creatorcontrib>Nolte, Robert T.</creatorcontrib><creatorcontrib>Wang, Liping</creatorcontrib><creatorcontrib>Ferris, Robert G.</creatorcontrib><creatorcontrib>Edelstein, Mark</creatorcontrib><creatorcontrib>Weaver, Kurt</creatorcontrib><creatorcontrib>Mathis, Amanda</creatorcontrib><creatorcontrib>Peat, Andrew</creatorcontrib><creatorcontrib>Argonne National Lab. 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Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rational Design of Potent Non-Nucleoside Inhibitors of HIV‑1 Reverse Transcriptase</atitle><jtitle>J. Med. Chem</jtitle><addtitle>J. Med. Chem</addtitle><date>2012-12-13</date><risdate>2012</risdate><volume>55</volume><issue>23</issue><spage>10601</spage><epage>10609</epage><pages>10601-10609</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50 < 1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>23137340</pmid><doi>10.1021/jm301294g</doi><tpages>9</tpages></addata></record> |
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| ispartof | J. Med. Chem, 2012-12, Vol.55 (23), p.10601-10609 |
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| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Crystallography, X-Ray Drug Design HIV Reverse Transcriptase - antagonists & inhibitors HIV-1 - drug effects Microbial Sensitivity Tests Models, Molecular Reverse Transcriptase Inhibitors - chemistry Reverse Transcriptase Inhibitors - pharmacology |
| title | Rational Design of Potent Non-Nucleoside Inhibitors of HIV‑1 Reverse Transcriptase |
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