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Ureidopeptide GLP-1 analogues with prolonged activity in vivo via signal bias and altered receptor trafficking.
Chem Sci. 2019 Nov 14; 10(42):9872-9879.CS

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.

Authors+Show Affiliations

UREkA - ImmuPharma Group , 2 rue Robert Escarpit , 33607 Pessac , France . Email: sebastien.goudreau@immupharma.com.UREkA - ImmuPharma Group , 2 rue Robert Escarpit , 33607 Pessac , France . Email: sebastien.goudreau@immupharma.com.UREkA - ImmuPharma Group , 2 rue Robert Escarpit , 33607 Pessac , France . Email: sebastien.goudreau@immupharma.com.UREkA - ImmuPharma Group , 2 rue Robert Escarpit , 33607 Pessac , France . Email: sebastien.goudreau@immupharma.com.Laboratoire d'Innovation Thérapeutique , UMR7200 CNRS-Université de Strasbourg , 74 route du Rhin , 67400 Illkirch , France.Laboratoire d'Innovation Thérapeutique , UMR7200 CNRS-Université de Strasbourg , 74 route du Rhin , 67400 Illkirch , France.Section of Cell Biology and Functional Genomics , Imperial College London , London W12 0NN , UK.Section of Investigative Medicine , Imperial College London , London W12 0NN , UK.Section of Investigative Medicine , Imperial College London , London W12 0NN , UK.Section of Cell Biology and Functional Genomics , Imperial College London , London W12 0NN , UK.Univ. Bordeaux , CNRS , CBMN , UMR 5248 , Institut Européen de Chimie et Biologie , 2 rue Robert Escarpit , 33607 Pessac , France . Email: g.guichard@iecb.u-bordeaux.fr.UREkA - ImmuPharma Group , 2 rue Robert Escarpit , 33607 Pessac , France . Email: sebastien.goudreau@immupharma.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32015811

Citation

Fremaux, Juliette, et al. "Ureidopeptide GLP-1 Analogues With Prolonged Activity in Vivo Via Signal Bias and Altered Receptor Trafficking." Chemical Science, vol. 10, no. 42, 2019, pp. 9872-9879.
Fremaux J, Venin C, Mauran L, et al. Ureidopeptide GLP-1 analogues with prolonged activity in vivo via signal bias and altered receptor trafficking. Chem Sci. 2019;10(42):9872-9879.
Fremaux, J., Venin, C., Mauran, L., Zimmer, R., Koensgen, F., Rognan, D., Bitsi, S., Lucey, M. A., Jones, B., Tomas, A., Guichard, G., & Goudreau, S. R. (2019). Ureidopeptide GLP-1 analogues with prolonged activity in vivo via signal bias and altered receptor trafficking. Chemical Science, 10(42), 9872-9879. https://doi.org/10.1039/c9sc02079a
Fremaux J, et al. Ureidopeptide GLP-1 Analogues With Prolonged Activity in Vivo Via Signal Bias and Altered Receptor Trafficking. Chem Sci. 2019 Nov 14;10(42):9872-9879. PubMed PMID: 32015811.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ureidopeptide GLP-1 analogues with prolonged activity in vivo via signal bias and altered receptor trafficking. AU - Fremaux,Juliette, AU - Venin,Claire, AU - Mauran,Laura, AU - Zimmer,Robert, AU - Koensgen,Florian, AU - Rognan,Didier, AU - Bitsi,Stavroula, AU - Lucey,Maria A, AU - Jones,Ben, AU - Tomas,Alejandra, AU - Guichard,Gilles, AU - Goudreau,Sébastien R, Y1 - 2019/09/11/ PY - 2019/04/26/received PY - 2019/08/27/accepted PY - 2020/2/5/entrez PY - 2020/2/6/pubmed PY - 2020/2/6/medline SP - 9872 EP - 9879 JF - Chemical science JO - Chem Sci VL - 10 IS - 42 N2 - 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. SN - 2041-6520 UR - https://www.unboundmedicine.com/medline/citation/32015811/Ureidopeptide_GLP-1_analogues_with_prolonged_activity_in_vivo_via_signal_bias_and_altered_receptor_trafficking L2 - https://doi.org/10.1039/c9sc02079a DB - PRIME DP - Unbound Medicine ER -
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