Ureidopeptide GLP-1 analogues with prolonged activity
Journal
Chemical science
ISSN: 2041-6520
Titre abrégé: Chem Sci
Pays: England
ID NLM: 101545951
Informations de publication
Date de publication:
14 Nov 2019
14 Nov 2019
Historique:
received:
26
04
2019
accepted:
27
08
2019
entrez:
5
2
2020
pubmed:
6
2
2020
medline:
6
2
2020
Statut:
epublish
Résumé
The high demand of the pharmaceutical industry for new modalities to address the diversification of biological targets with large surfaces of interaction led us to investigate the replacement of α-amino acid residues with ureido units at selected positions in peptides to improve potency and generate effective incretin mimics. Based on molecular dynamics simulations, N-terminally modified GLP-1 analogues with a ureido residue replacement at position 2 were synthesized and showed preservation of agonist activity while exhibiting a substantial increase in stability. This enabling platform was applied to exenatide and lixisenatide analogues to generate two new ureidopeptides with antidiabetic properties and longer duration of action. Further analyses demonstrated that the improvement was due mainly to differences in signal bias and trafficking of the GLP-1 receptor. This study demonstrates the efficacy of single α-amino acid substitution with ureido residues to design long lasting peptides.
Identifiants
pubmed: 32015811
doi: 10.1039/c9sc02079a
pii: c9sc02079a
pmc: PMC6977461
doi:
Types de publication
Journal Article
Langues
eng
Pagination
9872-9879Subventions
Organisme : Medical Research Council
ID : MR/K023667/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R010676/1
Pays : United Kingdom
Informations de copyright
This journal is © The Royal Society of Chemistry 2019.
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