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First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity
A series of 9-mer and 13-mer amide-bridged cyclic peptides derived from the linear prototype Ac-PKIIQSVGIS-Nle-K-Nle-NH2 (Toro et al. ChemBioChem2013) has been designed and synthesized by introduction of the lactam between amino acid side chains that are separated by one helical turn (i, i+4). All o...
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| Published in: | European journal of medicinal chemistry 2017-07, Vol.135, p.49-59 |
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| container_title | European journal of medicinal chemistry |
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| creator | Ruiz-Santaquiteria, Marta Sánchez-Murcia, Pedro A. Toro, Miguel A. de Lucio, Héctor Gutiérrez, Kilian Jesús de Castro, Sonia Carneiro, Filipa A.C. Gago, Federico Jiménez-Ruiz, Antonio Camarasa, María-José Velázquez, Sonsoles |
| description | A series of 9-mer and 13-mer amide-bridged cyclic peptides derived from the linear prototype Ac-PKIIQSVGIS-Nle-K-Nle-NH2 (Toro et al. ChemBioChem2013) has been designed and synthesized by introduction of the lactam between amino acid side chains that are separated by one helical turn (i, i+4). All of these compounds were tested in vitro as both dimerization and enzyme inhibitors of Leishmania infantum trypanothione reductase (Li-TryR). Three of the 13-mer cyclic peptide derivatives (3, 4 and 6) inhibited the oxidoreductase activity of Li-TryR in the low micromolar range and they also disrupted enzyme dimerization. Cyclic analogues 3 and 4 were more resistant to proteases than was the linear prototype. Furthermore, the most potent TryR inhibitors in the linear and cyclic series displayed potent in vitro activity against Leishmania infantum upon conjugation with cationic cell-penetrating peptides. To date, these conjugated peptides can be considered the first example of TryR dimerization inhibitors that are active in cell culture.
[Display omitted]
•Lactam-bridged peptides derived from linear prototypes are reported.•Potent inhibition of Li-TryR oxidoreductase activity and dimerization is described.•Increased proteolytic stability relative to the linear prototype is observed.•Conjugation with cell-penetrating peptides results in potent leishmanicidal activity.•The presence of the parent peptide sequence in conjugates is critical for activity. |
| doi_str_mv | 10.1016/j.ejmech.2017.04.020 |
| format | article |
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[Display omitted]
•Lactam-bridged peptides derived from linear prototypes are reported.•Potent inhibition of Li-TryR oxidoreductase activity and dimerization is described.•Increased proteolytic stability relative to the linear prototype is observed.•Conjugation with cell-penetrating peptides results in potent leishmanicidal activity.•The presence of the parent peptide sequence in conjugates is critical for activity.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2017.04.020</identifier><identifier>PMID: 28431354</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Antiprotozoal Agents - chemical synthesis ; Antiprotozoal Agents - chemistry ; Antiprotozoal Agents - pharmacology ; Cell Proliferation - drug effects ; Cell-penetrating peptides ; Cells, Cultured ; Dimerization ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Helix stabilization ; Leishmania infantum ; Leishmania infantum - cytology ; Leishmania infantum - drug effects ; Leishmania infantum - metabolism ; Molecular Dynamics Simulation ; Molecular Structure ; NADH, NADPH Oxidoreductases - antagonists & inhibitors ; NADH, NADPH Oxidoreductases - metabolism ; Peptides ; Peptides - chemical synthesis ; Peptides - chemistry ; Peptides - pharmacology ; Protein-protein interactions ; Structure-Activity Relationship ; Trypanothione reductase</subject><ispartof>European journal of medicinal chemistry, 2017-07, Vol.135, p.49-59</ispartof><rights>2017 The Authors</rights><rights>Copyright © 2017 The Authors. Published by Elsevier Masson SAS.. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-70a2b02d651cd92d66ae4d8fda5c19b6aa8638d76187d9b87eaea81ce37f8b223</citedby><cites>FETCH-LOGICAL-c408t-70a2b02d651cd92d66ae4d8fda5c19b6aa8638d76187d9b87eaea81ce37f8b223</cites><orcidid>0000-0003-2209-1751 ; 0000-0001-8238-3081</orcidid></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/28431354$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ruiz-Santaquiteria, Marta</creatorcontrib><creatorcontrib>Sánchez-Murcia, Pedro A.</creatorcontrib><creatorcontrib>Toro, Miguel A.</creatorcontrib><creatorcontrib>de Lucio, Héctor</creatorcontrib><creatorcontrib>Gutiérrez, Kilian Jesús</creatorcontrib><creatorcontrib>de Castro, Sonia</creatorcontrib><creatorcontrib>Carneiro, Filipa A.C.</creatorcontrib><creatorcontrib>Gago, Federico</creatorcontrib><creatorcontrib>Jiménez-Ruiz, Antonio</creatorcontrib><creatorcontrib>Camarasa, María-José</creatorcontrib><creatorcontrib>Velázquez, Sonsoles</creatorcontrib><title>First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>A series of 9-mer and 13-mer amide-bridged cyclic peptides derived from the linear prototype Ac-PKIIQSVGIS-Nle-K-Nle-NH2 (Toro et al. ChemBioChem2013) has been designed and synthesized by introduction of the lactam between amino acid side chains that are separated by one helical turn (i, i+4). All of these compounds were tested in vitro as both dimerization and enzyme inhibitors of Leishmania infantum trypanothione reductase (Li-TryR). Three of the 13-mer cyclic peptide derivatives (3, 4 and 6) inhibited the oxidoreductase activity of Li-TryR in the low micromolar range and they also disrupted enzyme dimerization. Cyclic analogues 3 and 4 were more resistant to proteases than was the linear prototype. Furthermore, the most potent TryR inhibitors in the linear and cyclic series displayed potent in vitro activity against Leishmania infantum upon conjugation with cationic cell-penetrating peptides. To date, these conjugated peptides can be considered the first example of TryR dimerization inhibitors that are active in cell culture.
[Display omitted]
•Lactam-bridged peptides derived from linear prototypes are reported.•Potent inhibition of Li-TryR oxidoreductase activity and dimerization is described.•Increased proteolytic stability relative to the linear prototype is observed.•Conjugation with cell-penetrating peptides results in potent leishmanicidal activity.•The presence of the parent peptide sequence in conjugates is critical for activity.</description><subject>Antiprotozoal Agents - chemical synthesis</subject><subject>Antiprotozoal Agents - chemistry</subject><subject>Antiprotozoal Agents - pharmacology</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell-penetrating peptides</subject><subject>Cells, Cultured</subject><subject>Dimerization</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Helix stabilization</subject><subject>Leishmania infantum</subject><subject>Leishmania infantum - cytology</subject><subject>Leishmania infantum - drug effects</subject><subject>Leishmania infantum - metabolism</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular Structure</subject><subject>NADH, NADPH Oxidoreductases - antagonists & inhibitors</subject><subject>NADH, NADPH Oxidoreductases - metabolism</subject><subject>Peptides</subject><subject>Peptides - chemical synthesis</subject><subject>Peptides - chemistry</subject><subject>Peptides - pharmacology</subject><subject>Protein-protein interactions</subject><subject>Structure-Activity Relationship</subject><subject>Trypanothione reductase</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNp9kcFu1DAQhi0EokvhDRDykUuC7TiO94KEKgpIK3GBszWxJ41XiRNsp7APwp1n4clw2dIjp5Fmvn9G9kfIS85qzrh6c6zxOKMda8F4VzNZM8EekR3vlK4a0crHZMeEaKpWNPKCPEvpyBhrFWNPyYXQsuFNK3fk57WPKVP8AfM6IV0GuuKavcNEM8QbzD7c0DwidX7GSH3IGAewf8kD-jTOEDyU_gAhbzPN8bRCWPLol4A0ottshoT0u88jXZeMIRf4969bn-NCS8ZPD1smCjb7Mjk9J08GmBK-uK-X5Ov1-y9XH6vD5w-frt4dKiuZzlXHQPRMONVy6_alKkDp9OCgtXzfKwCtGu06xXXn9r3uEBA0t9h0g-7L51yS1-e9a1y-bZiymX2yOE0QcNmS4XrPuVRCyoLKM2rjklLEwazRzxBPhjNzJ8QczVmIuRNimDRFSIm9ur-w9TO6h9A_AwV4ewawvPPWYzTJegwWnY9os3GL__-FP8b4o7U</recordid><startdate>20170728</startdate><enddate>20170728</enddate><creator>Ruiz-Santaquiteria, Marta</creator><creator>Sánchez-Murcia, Pedro A.</creator><creator>Toro, Miguel A.</creator><creator>de Lucio, Héctor</creator><creator>Gutiérrez, Kilian Jesús</creator><creator>de Castro, Sonia</creator><creator>Carneiro, Filipa A.C.</creator><creator>Gago, Federico</creator><creator>Jiménez-Ruiz, Antonio</creator><creator>Camarasa, María-José</creator><creator>Velázquez, Sonsoles</creator><general>Elsevier Masson SAS</general><scope>6I.</scope><scope>AAFTH</scope><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><orcidid>https://orcid.org/0000-0003-2209-1751</orcidid><orcidid>https://orcid.org/0000-0001-8238-3081</orcidid></search><sort><creationdate>20170728</creationdate><title>First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity</title><author>Ruiz-Santaquiteria, Marta ; Sánchez-Murcia, Pedro A. ; Toro, Miguel A. ; de Lucio, Héctor ; Gutiérrez, Kilian Jesús ; de Castro, Sonia ; Carneiro, Filipa A.C. ; Gago, Federico ; Jiménez-Ruiz, Antonio ; Camarasa, María-José ; Velázquez, Sonsoles</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-70a2b02d651cd92d66ae4d8fda5c19b6aa8638d76187d9b87eaea81ce37f8b223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Antiprotozoal Agents - chemical synthesis</topic><topic>Antiprotozoal Agents - chemistry</topic><topic>Antiprotozoal Agents - pharmacology</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell-penetrating peptides</topic><topic>Cells, Cultured</topic><topic>Dimerization</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Helix stabilization</topic><topic>Leishmania infantum</topic><topic>Leishmania infantum - cytology</topic><topic>Leishmania infantum - drug effects</topic><topic>Leishmania infantum - metabolism</topic><topic>Molecular Dynamics Simulation</topic><topic>Molecular Structure</topic><topic>NADH, NADPH Oxidoreductases - antagonists & inhibitors</topic><topic>NADH, NADPH Oxidoreductases - metabolism</topic><topic>Peptides</topic><topic>Peptides - chemical synthesis</topic><topic>Peptides - chemistry</topic><topic>Peptides - pharmacology</topic><topic>Protein-protein interactions</topic><topic>Structure-Activity Relationship</topic><topic>Trypanothione reductase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ruiz-Santaquiteria, Marta</creatorcontrib><creatorcontrib>Sánchez-Murcia, Pedro A.</creatorcontrib><creatorcontrib>Toro, Miguel A.</creatorcontrib><creatorcontrib>de Lucio, Héctor</creatorcontrib><creatorcontrib>Gutiérrez, Kilian Jesús</creatorcontrib><creatorcontrib>de Castro, Sonia</creatorcontrib><creatorcontrib>Carneiro, Filipa A.C.</creatorcontrib><creatorcontrib>Gago, Federico</creatorcontrib><creatorcontrib>Jiménez-Ruiz, Antonio</creatorcontrib><creatorcontrib>Camarasa, María-José</creatorcontrib><creatorcontrib>Velázquez, Sonsoles</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ruiz-Santaquiteria, Marta</au><au>Sánchez-Murcia, Pedro A.</au><au>Toro, Miguel A.</au><au>de Lucio, Héctor</au><au>Gutiérrez, Kilian Jesús</au><au>de Castro, Sonia</au><au>Carneiro, Filipa A.C.</au><au>Gago, Federico</au><au>Jiménez-Ruiz, Antonio</au><au>Camarasa, María-José</au><au>Velázquez, Sonsoles</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2017-07-28</date><risdate>2017</risdate><volume>135</volume><spage>49</spage><epage>59</epage><pages>49-59</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>A series of 9-mer and 13-mer amide-bridged cyclic peptides derived from the linear prototype Ac-PKIIQSVGIS-Nle-K-Nle-NH2 (Toro et al. ChemBioChem2013) has been designed and synthesized by introduction of the lactam between amino acid side chains that are separated by one helical turn (i, i+4). All of these compounds were tested in vitro as both dimerization and enzyme inhibitors of Leishmania infantum trypanothione reductase (Li-TryR). Three of the 13-mer cyclic peptide derivatives (3, 4 and 6) inhibited the oxidoreductase activity of Li-TryR in the low micromolar range and they also disrupted enzyme dimerization. Cyclic analogues 3 and 4 were more resistant to proteases than was the linear prototype. Furthermore, the most potent TryR inhibitors in the linear and cyclic series displayed potent in vitro activity against Leishmania infantum upon conjugation with cationic cell-penetrating peptides. To date, these conjugated peptides can be considered the first example of TryR dimerization inhibitors that are active in cell culture.
[Display omitted]
•Lactam-bridged peptides derived from linear prototypes are reported.•Potent inhibition of Li-TryR oxidoreductase activity and dimerization is described.•Increased proteolytic stability relative to the linear prototype is observed.•Conjugation with cell-penetrating peptides results in potent leishmanicidal activity.•The presence of the parent peptide sequence in conjugates is critical for activity.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>28431354</pmid><doi>10.1016/j.ejmech.2017.04.020</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-2209-1751</orcidid><orcidid>https://orcid.org/0000-0001-8238-3081</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antiprotozoal Agents - chemical synthesis Antiprotozoal Agents - chemistry Antiprotozoal Agents - pharmacology Cell Proliferation - drug effects Cell-penetrating peptides Cells, Cultured Dimerization Dose-Response Relationship, Drug Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Helix stabilization Leishmania infantum Leishmania infantum - cytology Leishmania infantum - drug effects Leishmania infantum - metabolism Molecular Dynamics Simulation Molecular Structure NADH, NADPH Oxidoreductases - antagonists & inhibitors NADH, NADPH Oxidoreductases - metabolism Peptides Peptides - chemical synthesis Peptides - chemistry Peptides - pharmacology Protein-protein interactions Structure-Activity Relationship Trypanothione reductase |
| title | First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity |
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