Abstract
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.
Highlights
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
Peptide YY (PYY1-36) is a 36 amino acid peptide that is co-released with GLP-1 from the L-cells in the distal gut in response to ingestion of nutrients[1,2] and is part of a family of peptides including neuropeptide Y (NPY) and pancreatic polypeptide (PP), which all share a common structural fold known as the PP-fold[3]
We synthesized a large series of PYY3-36 analogues (Table 1) in which we studied the half-life in minipigs, the NPY receptor potencies and binding properties for both human and porcine albumin as a function of fatty diacid derivatization
Summary
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 noncovalently associate the peptide to serum albumin 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. 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. More attractive from a pharmaceutical point of view, is the design of a P YY3-36 analogue displaying a much-prolonged half-life after administration by s.c. injection
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