Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin‑2 for Cardiovascular Diseases
The insulin-like peptide human relaxin-2 was identified as a hormone that, among other biological functions, mediates the hemodynamic changes occurring during pregnancy. Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been...
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| Veröffentlicht in: | Journal of medicinal chemistry 2021-02, Vol.64 (4), p.2139-2150 |
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| creator | Mallart, Sergio Ingenito, Raffaele Bianchi, Elisabetta Bresciani, Alberto Esposito, Simone Gallo, Mariana Magotti, Paola Monteagudo, Edith Orsatti, Laura Roversi, Daniela Santoprete, Alessia Tucci, Federica Veneziano, Maria Bartsch, Régine Boehm, Claudius Brasseur, Denis Bruneau, Patricia Corbier, Alain Froissant, Jacques Gauzy-Lazo, Laurence Gervat, Vincent Marguet, Frank Menguy, Isabelle Minoletti, Claire Nicolas, Marie-Françoise Pasquier, Olivier Poirier, Bruno Raux, Alexandre Riva, Laurence Janiak, Philip Strobel, Hartmut Duclos, Olivier Illiano, Stephane |
| description | The insulin-like peptide human relaxin-2 was identified as a hormone that, among other biological functions, mediates the hemodynamic changes occurring during pregnancy. Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been hampered by its short half-life and the need for intravenous administration limiting its use to intensive care units. In this study, we report the development of long-acting potent single-chain relaxin peptide mimetics. Modifications in the B-chain of relaxin, such as the introduction of specific mutations and the trimming of the sequence to an optimal size, resulted in potent, structurally simplified peptide agonists of the relaxin receptor Relaxin Family Peptide Receptor 1 (RXFP1) (e.g., 54). Introduction of suitable spacers and fatty acids led to the identification of single-chain lipidated peptide agonists of RXFP1, with sub-nanomolar activity, high subcutaneous bioavailability, extended half-lives, and in vivo efficacy (e.g., 64). |
| doi_str_mv | 10.1021/acs.jmedchem.0c01533 |
| format | Article |
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Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been hampered by its short half-life and the need for intravenous administration limiting its use to intensive care units. In this study, we report the development of long-acting potent single-chain relaxin peptide mimetics. Modifications in the B-chain of relaxin, such as the introduction of specific mutations and the trimming of the sequence to an optimal size, resulted in potent, structurally simplified peptide agonists of the relaxin receptor Relaxin Family Peptide Receptor 1 (RXFP1) (e.g., 54). Introduction of suitable spacers and fatty acids led to the identification of single-chain lipidated peptide agonists of RXFP1, with sub-nanomolar activity, high subcutaneous bioavailability, extended half-lives, and in vivo efficacy (e.g., 64).</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c01533</identifier><identifier>PMID: 33555858</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amino Acid Sequence ; Animals ; Cardiovascular Diseases ; Cell Line, Tumor ; Half-Life ; HEK293 Cells ; Humans ; Lipopeptides - genetics ; Lipopeptides - pharmacokinetics ; Lipopeptides - pharmacology ; Male ; Molecular Dynamics Simulation ; Molecular Structure ; Mutation ; Protein Subunits ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled - agonists ; Receptors, Peptide - agonists ; Relaxin - analogs & derivatives ; Relaxin - genetics ; Relaxin - pharmacology ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2021-02, Vol.64 (4), p.2139-2150</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-161b4e9e25aaf8b05374aef10a6f1a4d142181e4c5da5a1415aebefb48e0b1c33</citedby><cites>FETCH-LOGICAL-a348t-161b4e9e25aaf8b05374aef10a6f1a4d142181e4c5da5a1415aebefb48e0b1c33</cites><orcidid>0000-0001-9196-0493 ; 0000-0002-7902-2514 ; 0000-0002-8292-6346 ; 0000-0003-3991-0637 ; 0000-0002-6206-8284 ; 0000-0002-0161-9820 ; 0000-0001-6748-1732 ; 0000-0002-5430-9965 ; 0000-0002-5302-6912 ; 0000-0002-7109-7052 ; 0000-0003-1846-8683 ; 0000-0003-4491-603X</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/acs.jmedchem.0c01533$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01533$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33555858$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mallart, Sergio</creatorcontrib><creatorcontrib>Ingenito, Raffaele</creatorcontrib><creatorcontrib>Bianchi, Elisabetta</creatorcontrib><creatorcontrib>Bresciani, Alberto</creatorcontrib><creatorcontrib>Esposito, Simone</creatorcontrib><creatorcontrib>Gallo, Mariana</creatorcontrib><creatorcontrib>Magotti, Paola</creatorcontrib><creatorcontrib>Monteagudo, Edith</creatorcontrib><creatorcontrib>Orsatti, Laura</creatorcontrib><creatorcontrib>Roversi, Daniela</creatorcontrib><creatorcontrib>Santoprete, Alessia</creatorcontrib><creatorcontrib>Tucci, Federica</creatorcontrib><creatorcontrib>Veneziano, Maria</creatorcontrib><creatorcontrib>Bartsch, Régine</creatorcontrib><creatorcontrib>Boehm, Claudius</creatorcontrib><creatorcontrib>Brasseur, Denis</creatorcontrib><creatorcontrib>Bruneau, Patricia</creatorcontrib><creatorcontrib>Corbier, Alain</creatorcontrib><creatorcontrib>Froissant, Jacques</creatorcontrib><creatorcontrib>Gauzy-Lazo, Laurence</creatorcontrib><creatorcontrib>Gervat, Vincent</creatorcontrib><creatorcontrib>Marguet, Frank</creatorcontrib><creatorcontrib>Menguy, Isabelle</creatorcontrib><creatorcontrib>Minoletti, Claire</creatorcontrib><creatorcontrib>Nicolas, Marie-Françoise</creatorcontrib><creatorcontrib>Pasquier, Olivier</creatorcontrib><creatorcontrib>Poirier, Bruno</creatorcontrib><creatorcontrib>Raux, Alexandre</creatorcontrib><creatorcontrib>Riva, Laurence</creatorcontrib><creatorcontrib>Janiak, Philip</creatorcontrib><creatorcontrib>Strobel, Hartmut</creatorcontrib><creatorcontrib>Duclos, Olivier</creatorcontrib><creatorcontrib>Illiano, Stephane</creatorcontrib><title>Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin‑2 for Cardiovascular Diseases</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The insulin-like peptide human relaxin-2 was identified as a hormone that, among other biological functions, mediates the hemodynamic changes occurring during pregnancy. Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been hampered by its short half-life and the need for intravenous administration limiting its use to intensive care units. In this study, we report the development of long-acting potent single-chain relaxin peptide mimetics. Modifications in the B-chain of relaxin, such as the introduction of specific mutations and the trimming of the sequence to an optimal size, resulted in potent, structurally simplified peptide agonists of the relaxin receptor Relaxin Family Peptide Receptor 1 (RXFP1) (e.g., 54). 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Modifications in the B-chain of relaxin, such as the introduction of specific mutations and the trimming of the sequence to an optimal size, resulted in potent, structurally simplified peptide agonists of the relaxin receptor Relaxin Family Peptide Receptor 1 (RXFP1) (e.g., 54). 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| ispartof | Journal of medicinal chemistry, 2021-02, Vol.64 (4), p.2139-2150 |
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| source | ACS Publications; MEDLINE |
| subjects | Amino Acid Sequence Animals Cardiovascular Diseases Cell Line, Tumor Half-Life HEK293 Cells Humans Lipopeptides - genetics Lipopeptides - pharmacokinetics Lipopeptides - pharmacology Male Molecular Dynamics Simulation Molecular Structure Mutation Protein Subunits Rats Rats, Sprague-Dawley Receptors, G-Protein-Coupled - agonists Receptors, Peptide - agonists Relaxin - analogs & derivatives Relaxin - genetics Relaxin - pharmacology Structure-Activity Relationship |
| title | Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin‑2 for Cardiovascular Diseases |
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