The effect of fatty diacid acylation of human PYY3-36 on Y2 receptor potency and half-life in minipigs

Autor:	Rasmus Jorgensen, Luise Gram Schleiss, Kirsten Raun, Jacob Kofoed, Claus Bekker Jeppesen, Birgitte Schjellerup Wulff, Berit Østergaard Christoffersen, Jørgen Olsen, Lars Ynddal, Franziska Zosel, Ulrich Sensfuss, Johan F. Paulsson, Søren Østergaard, Jane Spetzler, Flemming S Nielsen
Jazyk:	angličtina
Rok vydání:	2021
Předmět:	Swine Science Serum albumin Peptide Lipid-anchored protein Medicinal chemistry CHO Cells Biochemistry Article Acylation Lipopeptides Cricetulus In vivo Cricetinae Potency Animals Humans Peptide YY Obesity chemistry.chemical_classification Pharmacology Lead optimization Multidisciplinary biology Drug discovery Fatty Acids Albumin Fatty acid Acetylation Liraglutide Receptors Neuropeptide Y Drug Combinations HEK293 Cells chemistry Drug delivery biology.protein Swine Miniature Medicine Female Anti-Obesity Agents Peptides Oligopeptides Half-Life Protein Binding
Zdroj:	Scientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) Scientific Reports
ISSN:	2045-2322
Popis:	Peptides are notoriously known to display very short in vivo half-lives often measured in minutes which in many cases greatly reduces or eliminates sufficient in vivo efficacy. To obtain long half-lives allowing for up to once-weekly dosing regimen, fatty acid acylation (lipidation) have been used to non-covalently associate the peptide to serum albumin thus serving as a circulating depot. This approach is generally considered in the scientific and patent community as a standard approach to protract almost any given peptide. However, it is not trivial to prolong the half-life of peptides by lipidation and still maintain high potency and good formulation properties. Here we show that attaching a fatty acid to the obesity-drug relevant peptide PYY3-36 is not sufficient for long pharmacokinetics (PK), since the position in the backbone, but also type of fatty acid and linker strongly influences PK and potency. Furthermore, understanding the proteolytic stability of the backbone is key to obtain long half-lives by lipidation, since backbone cleavage still occurs while associated to albumin. Having identified a PYY analogue with a sufficient half-life, we show that in combination with a GLP-1 analogue, liraglutide, additional weight loss can be achieved in the obese minipig model.
Databáze:	OpenAIRE
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