Evidence that a Prominent Cavity in the Coiled Coil of HIV Type 1 gp41 is an Attractive Drug Target
Synthetic C peptides, corresponding to the C helix of the HIV type 1 (HIV-1) gp41 envelope protein, are potent inhibitors of HIV-1 membrane fusion. One such peptide is in clinical trials. The crystal structure of the gp41 core, in its proposed fusion-active conformation, is a trimer of helical hairp...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1998-12, Vol.95 (26), p.15613-15617 |
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| creator | Chan, David C. Chutkowski, Christine T. Kim, Peter S. |
| description | Synthetic C peptides, corresponding to the C helix of the HIV type 1 (HIV-1) gp41 envelope protein, are potent inhibitors of HIV-1 membrane fusion. One such peptide is in clinical trials. The crystal structure of the gp41 core, in its proposed fusion-active conformation, is a trimer of helical hairpins in which three C helices pack against a central coiled coil. Each C helix shows especially prominent contacts with one of three symmetry-related, hydrophobic cavities on the surface of the coiled coil. We show that the inhibitory activity of the C peptide C34 depends on its ability to bind to this coiled-coil cavity. Moreover, examining a series of C34 peptide variants with modified cavity-binding residues, we find a linear relationship between the logarithm of the inhibitory potency and the stability of the corresponding helical-hairpin complexes. Our results provide strong evidence that this coiled-coil cavity is a good drug target and clarify the mechanism of C peptide inhibition. They also suggest simple, quantitative assays for the identification and evaluation of analogous inhibitors of HIV-1 entry. |
| doi_str_mv | 10.1073/pnas.95.26.15613 |
| format | Article |
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One such peptide is in clinical trials. The crystal structure of the gp41 core, in its proposed fusion-active conformation, is a trimer of helical hairpins in which three C helices pack against a central coiled coil. Each C helix shows especially prominent contacts with one of three symmetry-related, hydrophobic cavities on the surface of the coiled coil. We show that the inhibitory activity of the C peptide C34 depends on its ability to bind to this coiled-coil cavity. Moreover, examining a series of C34 peptide variants with modified cavity-binding residues, we find a linear relationship between the logarithm of the inhibitory potency and the stability of the corresponding helical-hairpin complexes. Our results provide strong evidence that this coiled-coil cavity is a good drug target and clarify the mechanism of C peptide inhibition. They also suggest simple, quantitative assays for the identification and evaluation of analogous inhibitors of HIV-1 entry.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.95.26.15613</identifier><identifier>PMID: 9861018</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>AIDS/HIV ; Amino Acid Sequence ; Amino Acid Substitution ; Anti-HIV Agents - chemical synthesis ; Anti-HIV Agents - chemistry ; Anti-HIV Agents - pharmacokinetics ; Binding Sites ; Biological Sciences ; Cell fusion ; Cell lines ; Cellular biology ; Circular Dichroism ; Drug Design ; HIV ; HIV 1 ; HIV Envelope Protein gp41 - chemistry ; HIV Envelope Protein gp41 - metabolism ; HIV-1 - drug effects ; HIV-1 - metabolism ; Human immunodeficiency virus ; Human immunodeficiency virus 1 ; Humans ; Infections ; Inhibitory concentration 50 ; Medical sciences ; Membrane Fusion ; Models, Molecular ; Molecular Sequence Data ; Peptide Fragments - chemical synthesis ; Peptide Fragments - chemistry ; Peptide Fragments - pharmacokinetics ; Peptides ; Protein Structure, Secondary ; Proteins ; Syncytia ; Tryptophan ; Viral morphology ; Viruses</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1998-12, Vol.95 (26), p.15613-15617</ispartof><rights>Copyright 1993-1998 National Academy of Sciences</rights><rights>Copyright National Academy of Sciences Dec 22, 1998</rights><rights>Copyright © 1998, The National Academy of Sciences 1998</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c523t-57b5c109be1c7ab93d621c8e05c12165947b061fcbe6e704abdc46b3ef4187093</citedby><cites>FETCH-LOGICAL-c523t-57b5c109be1c7ab93d621c8e05c12165947b061fcbe6e704abdc46b3ef4187093</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/95/26.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/46427$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/46427$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27923,27924,53790,53792,58016,58249</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9861018$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chan, David C.</creatorcontrib><creatorcontrib>Chutkowski, Christine T.</creatorcontrib><creatorcontrib>Kim, Peter S.</creatorcontrib><title>Evidence that a Prominent Cavity in the Coiled Coil of HIV Type 1 gp41 is an Attractive Drug Target</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Synthetic C peptides, corresponding to the C helix of the HIV type 1 (HIV-1) gp41 envelope protein, are potent inhibitors of HIV-1 membrane fusion. One such peptide is in clinical trials. The crystal structure of the gp41 core, in its proposed fusion-active conformation, is a trimer of helical hairpins in which three C helices pack against a central coiled coil. Each C helix shows especially prominent contacts with one of three symmetry-related, hydrophobic cavities on the surface of the coiled coil. We show that the inhibitory activity of the C peptide C34 depends on its ability to bind to this coiled-coil cavity. Moreover, examining a series of C34 peptide variants with modified cavity-binding residues, we find a linear relationship between the logarithm of the inhibitory potency and the stability of the corresponding helical-hairpin complexes. Our results provide strong evidence that this coiled-coil cavity is a good drug target and clarify the mechanism of C peptide inhibition. They also suggest simple, quantitative assays for the identification and evaluation of analogous inhibitors of HIV-1 entry.</description><subject>AIDS/HIV</subject><subject>Amino Acid Sequence</subject><subject>Amino Acid Substitution</subject><subject>Anti-HIV Agents - chemical synthesis</subject><subject>Anti-HIV Agents - chemistry</subject><subject>Anti-HIV Agents - pharmacokinetics</subject><subject>Binding Sites</subject><subject>Biological Sciences</subject><subject>Cell fusion</subject><subject>Cell lines</subject><subject>Cellular biology</subject><subject>Circular Dichroism</subject><subject>Drug Design</subject><subject>HIV</subject><subject>HIV 1</subject><subject>HIV Envelope Protein gp41 - chemistry</subject><subject>HIV Envelope Protein gp41 - metabolism</subject><subject>HIV-1 - drug effects</subject><subject>HIV-1 - metabolism</subject><subject>Human immunodeficiency virus</subject><subject>Human immunodeficiency virus 1</subject><subject>Humans</subject><subject>Infections</subject><subject>Inhibitory concentration 50</subject><subject>Medical sciences</subject><subject>Membrane Fusion</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Peptide Fragments - chemical synthesis</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - pharmacokinetics</subject><subject>Peptides</subject><subject>Protein Structure, Secondary</subject><subject>Proteins</subject><subject>Syncytia</subject><subject>Tryptophan</subject><subject>Viral morphology</subject><subject>Viruses</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUGP0zAQhSMEWroLd4SEsDggLikztuPEEpdVWdiVVoJD4Wo5jtN1lSbBdir679fdVhXLAU4jzfveaGZelr1CmCOU7OPY6zCXxZyKORYC2ZNshiAxF1zC02wGQMu84pQ_z85DWAOALCo4y85kJRCwmmXmausa2xtL4p2ORJPvfti43vaRLPTWxR1xfZIsWQyus81DIUNLrm9-kuVutATJauRIXCC6J5cxem2i21ry2U8rstR-ZeOL7Fmru2BfHutF9uPL1XJxnd9--3qzuLzNTUFZzIuyLkzavrZoSl1L1giKprKQuhRFIXlZg8DW1FbYEriuG8NFzWzLsSpBsovs02HuONUb25h0hNedGr3baL9Tg3bqsdK7O7UatopWIGmyvz_a_fBrsiGqjQvGdp3u7TAFJSQCAyz_C2KJvOJVkcB3f4HrYfJ9-oGigIwxjpggOEDGDyF4254WRlD7kNU-ZCULRYV6CDlZ3vx56MlwTDXpb4_63nlSH0348G9CtVPXRfs7JvT1AV2HOPgTywWnJbsHLjjC2A</recordid><startdate>19981222</startdate><enddate>19981222</enddate><creator>Chan, David C.</creator><creator>Chutkowski, Christine T.</creator><creator>Kim, Peter S.</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><general>The National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7T7</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>19981222</creationdate><title>Evidence that a Prominent Cavity in the Coiled Coil of HIV Type 1 gp41 is an Attractive Drug Target</title><author>Chan, David C. ; Chutkowski, Christine T. ; Kim, Peter S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c523t-57b5c109be1c7ab93d621c8e05c12165947b061fcbe6e704abdc46b3ef4187093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>AIDS/HIV</topic><topic>Amino Acid Sequence</topic><topic>Amino Acid Substitution</topic><topic>Anti-HIV Agents - chemical synthesis</topic><topic>Anti-HIV Agents - chemistry</topic><topic>Anti-HIV Agents - pharmacokinetics</topic><topic>Binding Sites</topic><topic>Biological Sciences</topic><topic>Cell fusion</topic><topic>Cell lines</topic><topic>Cellular biology</topic><topic>Circular Dichroism</topic><topic>Drug Design</topic><topic>HIV</topic><topic>HIV 1</topic><topic>HIV Envelope Protein gp41 - chemistry</topic><topic>HIV Envelope Protein gp41 - metabolism</topic><topic>HIV-1 - drug effects</topic><topic>HIV-1 - metabolism</topic><topic>Human immunodeficiency virus</topic><topic>Human immunodeficiency virus 1</topic><topic>Humans</topic><topic>Infections</topic><topic>Inhibitory concentration 50</topic><topic>Medical sciences</topic><topic>Membrane Fusion</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Peptide Fragments - chemical synthesis</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptide Fragments - pharmacokinetics</topic><topic>Peptides</topic><topic>Protein Structure, Secondary</topic><topic>Proteins</topic><topic>Syncytia</topic><topic>Tryptophan</topic><topic>Viral morphology</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chan, David C.</creatorcontrib><creatorcontrib>Chutkowski, Christine T.</creatorcontrib><creatorcontrib>Kim, Peter S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chan, David C.</au><au>Chutkowski, Christine T.</au><au>Kim, Peter S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evidence that a Prominent Cavity in the Coiled Coil of HIV Type 1 gp41 is an Attractive Drug Target</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1998-12-22</date><risdate>1998</risdate><volume>95</volume><issue>26</issue><spage>15613</spage><epage>15617</epage><pages>15613-15617</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Synthetic C peptides, corresponding to the C helix of the HIV type 1 (HIV-1) gp41 envelope protein, are potent inhibitors of HIV-1 membrane fusion. One such peptide is in clinical trials. The crystal structure of the gp41 core, in its proposed fusion-active conformation, is a trimer of helical hairpins in which three C helices pack against a central coiled coil. Each C helix shows especially prominent contacts with one of three symmetry-related, hydrophobic cavities on the surface of the coiled coil. We show that the inhibitory activity of the C peptide C34 depends on its ability to bind to this coiled-coil cavity. Moreover, examining a series of C34 peptide variants with modified cavity-binding residues, we find a linear relationship between the logarithm of the inhibitory potency and the stability of the corresponding helical-hairpin complexes. Our results provide strong evidence that this coiled-coil cavity is a good drug target and clarify the mechanism of C peptide inhibition. 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| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1998-12, Vol.95 (26), p.15613-15617 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_jstor_primary_46427 |
| source | MEDLINE; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | AIDS/HIV Amino Acid Sequence Amino Acid Substitution Anti-HIV Agents - chemical synthesis Anti-HIV Agents - chemistry Anti-HIV Agents - pharmacokinetics Binding Sites Biological Sciences Cell fusion Cell lines Cellular biology Circular Dichroism Drug Design HIV HIV 1 HIV Envelope Protein gp41 - chemistry HIV Envelope Protein gp41 - metabolism HIV-1 - drug effects HIV-1 - metabolism Human immunodeficiency virus Human immunodeficiency virus 1 Humans Infections Inhibitory concentration 50 Medical sciences Membrane Fusion Models, Molecular Molecular Sequence Data Peptide Fragments - chemical synthesis Peptide Fragments - chemistry Peptide Fragments - pharmacokinetics Peptides Protein Structure, Secondary Proteins Syncytia Tryptophan Viral morphology Viruses |
| title | Evidence that a Prominent Cavity in the Coiled Coil of HIV Type 1 gp41 is an Attractive Drug Target |
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