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A Potent Cyclic Peptide Targeting SPSB2 Protein as a Potential Anti-infective Agent
The protein SPSB2 mediates proteosomal degradation of inducible nitric oxide synthase (iNOS). Inhibitors of SPSB2–iNOS interaction may prolong the lifetime of iNOS and thereby enhance the killing of persistent pathogens. We have designed a cyclic peptide, Ac-c[CVDINNNC]-NH2, containing the key seque...
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| Published in: | Journal of medicinal chemistry 2014-08, Vol.57 (16), p.7006-7015 |
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| Main Authors: | , , , , , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-a315t-2c774ace521ea11ee89ee209ce2218c2acb8f6c9aac62cc67be9d915cf86d57d3 |
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| cites | cdi_FETCH-LOGICAL-a315t-2c774ace521ea11ee89ee209ce2218c2acb8f6c9aac62cc67be9d915cf86d57d3 |
| container_end_page | 7015 |
| container_issue | 16 |
| container_start_page | 7006 |
| container_title | Journal of medicinal chemistry |
| container_volume | 57 |
| creator | Yap, Beow Keat Leung, Eleanor W. W Yagi, Hiromasa Galea, Charles A Chhabra, Sandeep Chalmers, David K Nicholson, Sandra E Thompson, Philip E Norton, Raymond S |
| description | The protein SPSB2 mediates proteosomal degradation of inducible nitric oxide synthase (iNOS). Inhibitors of SPSB2–iNOS interaction may prolong the lifetime of iNOS and thereby enhance the killing of persistent pathogens. We have designed a cyclic peptide, Ac-c[CVDINNNC]-NH2, containing the key sequence motif mediating the SPSB2–iNOS interaction, which binds to the iNOS binding site on SPSB2 with a K d of 4.4 nM, as shown by SPR, [1H,15N]-HSQC, and 19F NMR. An in vitro assay on macrophage cell lysates showed complete inhibition of SPSB2–iNOS interactions by the cyclic peptide. Furthermore, its solution structure closely matched (backbone rmsd 1.21 Å) that of the SPSB2-bound linear DINNN peptide. The designed peptide was resistant to degradation by the proteases pepsin, trypsin, and chymotrypsin and stable in human plasma. This cyclic peptide exemplifies potentially a new class of anti-infective agents that acts on the host innate response, thereby avoiding the development of pathogen resistance. |
| doi_str_mv | 10.1021/jm500596j |
| format | article |
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W ; Yagi, Hiromasa ; Galea, Charles A ; Chhabra, Sandeep ; Chalmers, David K ; Nicholson, Sandra E ; Thompson, Philip E ; Norton, Raymond S</creator><creatorcontrib>Yap, Beow Keat ; Leung, Eleanor W. W ; Yagi, Hiromasa ; Galea, Charles A ; Chhabra, Sandeep ; Chalmers, David K ; Nicholson, Sandra E ; Thompson, Philip E ; Norton, Raymond S</creatorcontrib><description>The protein SPSB2 mediates proteosomal degradation of inducible nitric oxide synthase (iNOS). Inhibitors of SPSB2–iNOS interaction may prolong the lifetime of iNOS and thereby enhance the killing of persistent pathogens. We have designed a cyclic peptide, Ac-c[CVDINNNC]-NH2, containing the key sequence motif mediating the SPSB2–iNOS interaction, which binds to the iNOS binding site on SPSB2 with a K d of 4.4 nM, as shown by SPR, [1H,15N]-HSQC, and 19F NMR. An in vitro assay on macrophage cell lysates showed complete inhibition of SPSB2–iNOS interactions by the cyclic peptide. Furthermore, its solution structure closely matched (backbone rmsd 1.21 Å) that of the SPSB2-bound linear DINNN peptide. The designed peptide was resistant to degradation by the proteases pepsin, trypsin, and chymotrypsin and stable in human plasma. This cyclic peptide exemplifies potentially a new class of anti-infective agents that acts on the host innate response, thereby avoiding the development of pathogen resistance.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm500596j</identifier><identifier>PMID: 25068993</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Anti-Infective Agents - chemistry ; Anti-Infective Agents - pharmacology ; Binding Sites ; Humans ; Immunity, Innate - drug effects ; Macrophages - drug effects ; Macrophages - metabolism ; Magnetic Resonance Spectroscopy ; Mice ; Molecular Targeted Therapy ; Nitric Oxide Synthase Type II - metabolism ; Peptides, Cyclic - blood ; Peptides, Cyclic - chemistry ; Peptides, Cyclic - metabolism ; Peptides, Cyclic - pharmacology ; Protein Conformation ; Protein Stability ; Protein Transport ; Suppressor of Cytokine Signaling Proteins - chemistry ; Suppressor of Cytokine Signaling Proteins - metabolism ; Surface Plasmon Resonance</subject><ispartof>Journal of medicinal chemistry, 2014-08, Vol.57 (16), p.7006-7015</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-2c774ace521ea11ee89ee209ce2218c2acb8f6c9aac62cc67be9d915cf86d57d3</citedby><cites>FETCH-LOGICAL-a315t-2c774ace521ea11ee89ee209ce2218c2acb8f6c9aac62cc67be9d915cf86d57d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25068993$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yap, Beow Keat</creatorcontrib><creatorcontrib>Leung, Eleanor W. 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We have designed a cyclic peptide, Ac-c[CVDINNNC]-NH2, containing the key sequence motif mediating the SPSB2–iNOS interaction, which binds to the iNOS binding site on SPSB2 with a K d of 4.4 nM, as shown by SPR, [1H,15N]-HSQC, and 19F NMR. An in vitro assay on macrophage cell lysates showed complete inhibition of SPSB2–iNOS interactions by the cyclic peptide. Furthermore, its solution structure closely matched (backbone rmsd 1.21 Å) that of the SPSB2-bound linear DINNN peptide. The designed peptide was resistant to degradation by the proteases pepsin, trypsin, and chymotrypsin and stable in human plasma. This cyclic peptide exemplifies potentially a new class of anti-infective agents that acts on the host innate response, thereby avoiding the development of pathogen resistance.</description><subject>Animals</subject><subject>Anti-Infective Agents - chemistry</subject><subject>Anti-Infective Agents - pharmacology</subject><subject>Binding Sites</subject><subject>Humans</subject><subject>Immunity, Innate - drug effects</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - metabolism</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Mice</subject><subject>Molecular Targeted Therapy</subject><subject>Nitric Oxide Synthase Type II - metabolism</subject><subject>Peptides, Cyclic - blood</subject><subject>Peptides, Cyclic - chemistry</subject><subject>Peptides, Cyclic - metabolism</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Protein Conformation</subject><subject>Protein Stability</subject><subject>Protein Transport</subject><subject>Suppressor of Cytokine Signaling Proteins - chemistry</subject><subject>Suppressor of Cytokine Signaling Proteins - metabolism</subject><subject>Surface Plasmon Resonance</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNptkEtLw0AUhQdRbK0u_AMyG0EX0ZmbTpJZ1uILCgZa12F6c1Mm5FEzidB_70hrV64OXL5z4H6MXUvxIAXIx7JWQigdlSdsLBWIYJqI6SkbCwEQQAThiF04VwohQgnhORuBElGidThmyxlP256ans93WFnkKW17mxNfmW5DvW02fJkun4Cnncdsw43j5lCxpuIzH4FtCsLefhOfbfz9kp0VpnJ0dcgJ-3x5Xs3fgsXH6_t8tghMKFUfAMbx1CApkGSkJEo0EQiNBCATBIPrpIhQG4MRIEbxmnSupcIiiXIV5-GE3e13t137NZDrs9o6pKoyDbWDy6RSibcRh9qj93sUu9a5jops29nadLtMiuzXYXZ06Nmbw-ywrik_kn_SPHC7Bwy6rGyHrvFf_jP0AzEwd50</recordid><startdate>20140828</startdate><enddate>20140828</enddate><creator>Yap, Beow Keat</creator><creator>Leung, Eleanor W. 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W</creatorcontrib><creatorcontrib>Yagi, Hiromasa</creatorcontrib><creatorcontrib>Galea, Charles A</creatorcontrib><creatorcontrib>Chhabra, Sandeep</creatorcontrib><creatorcontrib>Chalmers, David K</creatorcontrib><creatorcontrib>Nicholson, Sandra E</creatorcontrib><creatorcontrib>Thompson, Philip E</creatorcontrib><creatorcontrib>Norton, Raymond 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>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yap, Beow Keat</au><au>Leung, Eleanor W. W</au><au>Yagi, Hiromasa</au><au>Galea, Charles A</au><au>Chhabra, Sandeep</au><au>Chalmers, David K</au><au>Nicholson, Sandra E</au><au>Thompson, Philip E</au><au>Norton, Raymond S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Potent Cyclic Peptide Targeting SPSB2 Protein as a Potential Anti-infective Agent</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2014-08-28</date><risdate>2014</risdate><volume>57</volume><issue>16</issue><spage>7006</spage><epage>7015</epage><pages>7006-7015</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>The protein SPSB2 mediates proteosomal degradation of inducible nitric oxide synthase (iNOS). Inhibitors of SPSB2–iNOS interaction may prolong the lifetime of iNOS and thereby enhance the killing of persistent pathogens. We have designed a cyclic peptide, Ac-c[CVDINNNC]-NH2, containing the key sequence motif mediating the SPSB2–iNOS interaction, which binds to the iNOS binding site on SPSB2 with a K d of 4.4 nM, as shown by SPR, [1H,15N]-HSQC, and 19F NMR. An in vitro assay on macrophage cell lysates showed complete inhibition of SPSB2–iNOS interactions by the cyclic peptide. Furthermore, its solution structure closely matched (backbone rmsd 1.21 Å) that of the SPSB2-bound linear DINNN peptide. The designed peptide was resistant to degradation by the proteases pepsin, trypsin, and chymotrypsin and stable in human plasma. This cyclic peptide exemplifies potentially a new class of anti-infective agents that acts on the host innate response, thereby avoiding the development of pathogen resistance.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>25068993</pmid><doi>10.1021/jm500596j</doi><tpages>10</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2014-08, Vol.57 (16), p.7006-7015 |
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| language | eng |
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| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Animals Anti-Infective Agents - chemistry Anti-Infective Agents - pharmacology Binding Sites Humans Immunity, Innate - drug effects Macrophages - drug effects Macrophages - metabolism Magnetic Resonance Spectroscopy Mice Molecular Targeted Therapy Nitric Oxide Synthase Type II - metabolism Peptides, Cyclic - blood Peptides, Cyclic - chemistry Peptides, Cyclic - metabolism Peptides, Cyclic - pharmacology Protein Conformation Protein Stability Protein Transport Suppressor of Cytokine Signaling Proteins - chemistry Suppressor of Cytokine Signaling Proteins - metabolism Surface Plasmon Resonance |
| title | A Potent Cyclic Peptide Targeting SPSB2 Protein as a Potential Anti-infective Agent |
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