Functional and Structural Characterization of 2‑Amino-4-phenylthiazole Inhibitors of the HIV‑1 Nucleocapsid Protein with Antiviral Activity
The nucleocapsid protein (NC) is a highly conserved protein in diverse HIV-1 subtypes that plays a central role in virus replication, mainly by interacting with conserved nucleic acid sequences. NC is considered a highly profitable drug target to inhibit multiple steps in the HIV-1 life cycle with j...
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| Veröffentlicht in: | ACS chemical biology 2014-09, Vol.9 (9), p.1950-1955 |
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| creator | Mori, Mattia Nucci, Alessandro Lang, Maria Chiara Dasso Humbert, Nicolas Boudier, Christian Debaene, Francois Sanglier-Cianferani, Sarah Catala, Marjorie Schult-Dietrich, Patricia Dietrich, Ursula Tisné, Carine Mely, Yves Botta, Maurizio |
| description | The nucleocapsid protein (NC) is a highly conserved protein in diverse HIV-1 subtypes that plays a central role in virus replication, mainly by interacting with conserved nucleic acid sequences. NC is considered a highly profitable drug target to inhibit multiple steps in the HIV-1 life cycle with just one compound, a unique property not shown by any of the other antiretroviral classes. However, most of NC inhibitors developed so far act through an unspecific and potentially toxic mechanism (zinc ejection) and are mainly being investigated as topical microbicides. In an effort to provide specific NC inhibitors that compete for the binding of nucleic acids to NC, here we combined molecular modeling, organic synthesis, biophysical studies, NMR spectroscopy, and antiviral assays to design, synthesize, and characterize an efficient NC inhibitor endowed with antiviral activity in vitro, a desirable property for the development of efficient antiretroviral lead compounds. |
| doi_str_mv | 10.1021/cb500316h |
| format | Article |
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NC is considered a highly profitable drug target to inhibit multiple steps in the HIV-1 life cycle with just one compound, a unique property not shown by any of the other antiretroviral classes. However, most of NC inhibitors developed so far act through an unspecific and potentially toxic mechanism (zinc ejection) and are mainly being investigated as topical microbicides. In an effort to provide specific NC inhibitors that compete for the binding of nucleic acids to NC, here we combined molecular modeling, organic synthesis, biophysical studies, NMR spectroscopy, and antiviral assays to design, synthesize, and characterize an efficient NC inhibitor endowed with antiviral activity in vitro, a desirable property for the development of efficient antiretroviral lead compounds.</description><identifier>ISSN: 1554-8929</identifier><identifier>EISSN: 1554-8937</identifier><identifier>DOI: 10.1021/cb500316h</identifier><identifier>PMID: 24988251</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Anti-HIV Agents - chemical synthesis ; Anti-HIV Agents - chemistry ; Anti-HIV Agents - pharmacology ; Calorimetry - methods ; Chemistry Techniques, Synthetic ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical - methods ; HeLa Cells - drug effects ; HeLa Cells - virology ; HIV-1 - chemistry ; HIV-1 - drug effects ; Humans ; Life Sciences ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Docking Simulation ; Nucleocapsid Proteins - antagonists & inhibitors ; Nucleocapsid Proteins - metabolism ; Structure-Activity Relationship ; Thiazoles - chemistry</subject><ispartof>ACS chemical biology, 2014-09, Vol.9 (9), p.1950-1955</ispartof><rights>Copyright © 2014 American Chemical Society</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a384t-e1d1babde3e7c5e84d1a9e8b1da76525695ff3541795cff5e2887d276435d3023</citedby><cites>FETCH-LOGICAL-a384t-e1d1babde3e7c5e84d1a9e8b1da76525695ff3541795cff5e2887d276435d3023</cites><orcidid>0000-0003-4013-4129</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/cb500316h$$EPDF$$P50$$Gacs$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/cb500316h$$EHTML$$P50$$Gacs$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,2763,27074,27922,27923,56736,56786</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24988251$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-01075936$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Mori, Mattia</creatorcontrib><creatorcontrib>Nucci, Alessandro</creatorcontrib><creatorcontrib>Lang, Maria Chiara Dasso</creatorcontrib><creatorcontrib>Humbert, Nicolas</creatorcontrib><creatorcontrib>Boudier, Christian</creatorcontrib><creatorcontrib>Debaene, Francois</creatorcontrib><creatorcontrib>Sanglier-Cianferani, Sarah</creatorcontrib><creatorcontrib>Catala, Marjorie</creatorcontrib><creatorcontrib>Schult-Dietrich, Patricia</creatorcontrib><creatorcontrib>Dietrich, Ursula</creatorcontrib><creatorcontrib>Tisné, Carine</creatorcontrib><creatorcontrib>Mely, Yves</creatorcontrib><creatorcontrib>Botta, Maurizio</creatorcontrib><title>Functional and Structural Characterization of 2‑Amino-4-phenylthiazole Inhibitors of the HIV‑1 Nucleocapsid Protein with Antiviral Activity</title><title>ACS chemical biology</title><addtitle>ACS Chem. 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Biol</addtitle><date>2014-09-19</date><risdate>2014</risdate><volume>9</volume><issue>9</issue><spage>1950</spage><epage>1955</epage><pages>1950-1955</pages><issn>1554-8929</issn><eissn>1554-8937</eissn><abstract>The nucleocapsid protein (NC) is a highly conserved protein in diverse HIV-1 subtypes that plays a central role in virus replication, mainly by interacting with conserved nucleic acid sequences. NC is considered a highly profitable drug target to inhibit multiple steps in the HIV-1 life cycle with just one compound, a unique property not shown by any of the other antiretroviral classes. However, most of NC inhibitors developed so far act through an unspecific and potentially toxic mechanism (zinc ejection) and are mainly being investigated as topical microbicides. 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| ispartof | ACS chemical biology, 2014-09, Vol.9 (9), p.1950-1955 |
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| source | MEDLINE; ACS Publications |
| subjects | Anti-HIV Agents - chemical synthesis Anti-HIV Agents - chemistry Anti-HIV Agents - pharmacology Calorimetry - methods Chemistry Techniques, Synthetic Dose-Response Relationship, Drug Drug Evaluation, Preclinical - methods HeLa Cells - drug effects HeLa Cells - virology HIV-1 - chemistry HIV-1 - drug effects Humans Life Sciences Magnetic Resonance Spectroscopy Models, Molecular Molecular Docking Simulation Nucleocapsid Proteins - antagonists & inhibitors Nucleocapsid Proteins - metabolism Structure-Activity Relationship Thiazoles - chemistry |
| title | Functional and Structural Characterization of 2‑Amino-4-phenylthiazole Inhibitors of the HIV‑1 Nucleocapsid Protein with Antiviral Activity |
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