Synthetic short-chain peptide analogues of H1 relaxin lack affinity for the RXFP1 receptor and relaxin-like bioactivity. Clues to a better understanding of relaxin agonist design
The peptide hormone relaxin (RLX), also available as clinical-grade recombinant protein (serelaxin), holds great promise as a cardiovascular and anti-fibrotic agent but is limited by the pharmacokinetic issues common to all peptide drugs. In this study, by a computational modelling chemistry approac...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-08-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.942178/full |
| _version_ | 1811309958473449472 |
|---|---|
| author | Annunziata D'Ercole Annunziata D'Ercole Silvia Nistri Lorenzo Pacini Lorenzo Pacini Alfonso Carotenuto Federica Santoro Anna Maria Papini Anna Maria Papini Ross A. D. Bathgate Daniele Bani Paolo Rovero Paolo Rovero |
| author_facet | Annunziata D'Ercole Annunziata D'Ercole Silvia Nistri Lorenzo Pacini Lorenzo Pacini Alfonso Carotenuto Federica Santoro Anna Maria Papini Anna Maria Papini Ross A. D. Bathgate Daniele Bani Paolo Rovero Paolo Rovero |
| author_sort | Annunziata D'Ercole |
| collection | DOAJ |
| description | The peptide hormone relaxin (RLX), also available as clinical-grade recombinant protein (serelaxin), holds great promise as a cardiovascular and anti-fibrotic agent but is limited by the pharmacokinetic issues common to all peptide drugs. In this study, by a computational modelling chemistry approach, we have synthesized and tested a set of low molecular weight peptides based on the putative receptor-binding domain of the B chain of human H1 RLX isoform, with the objective to obtain RLX analogues with improved pharmacokinetic features. Some of them were stabilized to induce the appropriate 3-D conformation by intra-chain tri-azolic staples, which should theoretically enhance their resistance to digestive enzymes making them suited for oral administration. Despite these favourable premises, none of these H1 peptides, either linear or stapled, revealed a sufficient affinity to the specific RLX receptor RXFP1. Moreover, none of them was endowed with any RLX-like biological effects in RXFP1-expressing THP-1 human monocytic cells and mouse NIH-3T3-derived myofibroblasts in in vitro culture, in terms of significantly relevant cAMP elevation and ERK1/2 phosphorylation, which represent two major signal transduction events downstream RXFP1 activation. This was at variance with authentic serelaxin, which induced a clear-cut, significant activation of both these classical RLX signaling pathways. Albeit negative, the results of this study offer additional information about the structural requirements that new peptide therapeutics shall possess to effectively behave as RXFP1 agonists and RLX analogues. |
| first_indexed | 2024-04-13T09:51:23Z |
| format | Article |
| id | doaj.art-df68676b7ec8426f970ad17c8d091f2b |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T09:51:23Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-df68676b7ec8426f970ad17c8d091f2b2022-12-22T02:51:36ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-08-011310.3389/fphar.2022.942178942178Synthetic short-chain peptide analogues of H1 relaxin lack affinity for the RXFP1 receptor and relaxin-like bioactivity. Clues to a better understanding of relaxin agonist designAnnunziata D'Ercole0Annunziata D'Ercole1Silvia Nistri2Lorenzo Pacini3Lorenzo Pacini4Alfonso Carotenuto5Federica Santoro6Anna Maria Papini7Anna Maria Papini8Ross A. D. Bathgate9Daniele Bani10Paolo Rovero11Paolo Rovero12Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology, University of Florence, Florence, ItalyDepartment of Chemistry “Ugo Schiff”, University of Florence, Florence, ItalyResearch Unit of Histology & Embryology, Department of Experimental & Clinical Medicine, University of Florence, Florence, ItalyInterdepartmental Research Unit of Peptide and Protein Chemistry and Biology, University of Florence, Florence, ItalyDepartment of Chemistry “Ugo Schiff”, University of Florence, Florence, ItalyDepartment of Pharmacy, University of Naples Federico II, Naples, ItalyDepartment of Pharmacy, University of Naples Federico II, Naples, ItalyInterdepartmental Research Unit of Peptide and Protein Chemistry and Biology, University of Florence, Florence, ItalyDepartment of Chemistry “Ugo Schiff”, University of Florence, Florence, ItalyFlorey Institute of Neuroscience and Mental Health and Department of Biochemistry and Pharmacology, Unviversity of Melbourne, Melbourne, VIC, AustraliaResearch Unit of Histology & Embryology, Department of Experimental & Clinical Medicine, University of Florence, Florence, ItalyInterdepartmental Research Unit of Peptide and Protein Chemistry and Biology, University of Florence, Florence, ItalyDepartment of NeuroFarBa, University of Florence, Florence, ItalyThe peptide hormone relaxin (RLX), also available as clinical-grade recombinant protein (serelaxin), holds great promise as a cardiovascular and anti-fibrotic agent but is limited by the pharmacokinetic issues common to all peptide drugs. In this study, by a computational modelling chemistry approach, we have synthesized and tested a set of low molecular weight peptides based on the putative receptor-binding domain of the B chain of human H1 RLX isoform, with the objective to obtain RLX analogues with improved pharmacokinetic features. Some of them were stabilized to induce the appropriate 3-D conformation by intra-chain tri-azolic staples, which should theoretically enhance their resistance to digestive enzymes making them suited for oral administration. Despite these favourable premises, none of these H1 peptides, either linear or stapled, revealed a sufficient affinity to the specific RLX receptor RXFP1. Moreover, none of them was endowed with any RLX-like biological effects in RXFP1-expressing THP-1 human monocytic cells and mouse NIH-3T3-derived myofibroblasts in in vitro culture, in terms of significantly relevant cAMP elevation and ERK1/2 phosphorylation, which represent two major signal transduction events downstream RXFP1 activation. This was at variance with authentic serelaxin, which induced a clear-cut, significant activation of both these classical RLX signaling pathways. Albeit negative, the results of this study offer additional information about the structural requirements that new peptide therapeutics shall possess to effectively behave as RXFP1 agonists and RLX analogues.https://www.frontiersin.org/articles/10.3389/fphar.2022.942178/fullrelaxinRXFP1relaxin analoguescAMPERK1/2RXFP1 agonists |
| spellingShingle | Annunziata D'Ercole Annunziata D'Ercole Silvia Nistri Lorenzo Pacini Lorenzo Pacini Alfonso Carotenuto Federica Santoro Anna Maria Papini Anna Maria Papini Ross A. D. Bathgate Daniele Bani Paolo Rovero Paolo Rovero Synthetic short-chain peptide analogues of H1 relaxin lack affinity for the RXFP1 receptor and relaxin-like bioactivity. Clues to a better understanding of relaxin agonist design Frontiers in Pharmacology relaxin RXFP1 relaxin analogues cAMP ERK1/2 RXFP1 agonists |
| title | Synthetic short-chain peptide analogues of H1 relaxin lack affinity for the RXFP1 receptor and relaxin-like bioactivity. Clues to a better understanding of relaxin agonist design |
| title_full | Synthetic short-chain peptide analogues of H1 relaxin lack affinity for the RXFP1 receptor and relaxin-like bioactivity. Clues to a better understanding of relaxin agonist design |
| title_fullStr | Synthetic short-chain peptide analogues of H1 relaxin lack affinity for the RXFP1 receptor and relaxin-like bioactivity. Clues to a better understanding of relaxin agonist design |
| title_full_unstemmed | Synthetic short-chain peptide analogues of H1 relaxin lack affinity for the RXFP1 receptor and relaxin-like bioactivity. Clues to a better understanding of relaxin agonist design |
| title_short | Synthetic short-chain peptide analogues of H1 relaxin lack affinity for the RXFP1 receptor and relaxin-like bioactivity. Clues to a better understanding of relaxin agonist design |
| title_sort | synthetic short chain peptide analogues of h1 relaxin lack affinity for the rxfp1 receptor and relaxin like bioactivity clues to a better understanding of relaxin agonist design |
| topic | relaxin RXFP1 relaxin analogues cAMP ERK1/2 RXFP1 agonists |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.942178/full |
| work_keys_str_mv | AT annunziatadercole syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT annunziatadercole syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT silvianistri syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT lorenzopacini syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT lorenzopacini syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT alfonsocarotenuto syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT federicasantoro syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT annamariapapini syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT annamariapapini syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT rossadbathgate syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT danielebani syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT paolorovero syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign AT paolorovero syntheticshortchainpeptideanaloguesofh1relaxinlackaffinityfortherxfp1receptorandrelaxinlikebioactivitycluestoabetterunderstandingofrelaxinagonistdesign |