Abstract
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.
Highlights
Backbone modi cations are a powerful strategy to improve peptide properties as they generally ameliorate their protection against proteolysis and their duration of action.[1,2] Such an approach is far from trivial as modifying the backbone of peptides has generally drastic negative impacts on binding properties, and potency
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 a-amino acid residues with ureido units at selected positions in peptides to improve potency and generate effective incretin mimics
This study demonstrates the efficacy of single aamino acid substitution with ureido residues to design long lasting peptides
Summary
Backbone modi cations are a powerful strategy to improve peptide properties as they generally ameliorate their protection against proteolysis and their duration of action.[1,2] Such an approach is far from trivial as modifying the backbone of peptides has generally drastic negative impacts on binding properties, and potency. Aza-amino acids[3,4] and b-amino acids[5,6,7] have proved to be efficient a-amino acid substitutions. Despite the potential of these approaches, new enabling platforms based on backbone modi cations are still needed to meet the increasingly demanding requirements of the pharmaceutical industry in peptide mimicry.[8]. Protein-dependent cAMP signalling and altered GLP-1R trafficking
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