1. Rational Development of Stable PYY 3-36 Peptide Y 2 Receptor Agonists.
- Author
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Poulsen C, Pedersen MØ, Wahlund PO, Sjölander A, Thomsen JK, Conde-Frieboes KW, Paulsson JF, Wulff BS, and Østergaard S
- Subjects
- Asparagine chemistry, Drug Development, HEK293 Cells, Humans, Peptide Fragments pharmacology, Peptide YY pharmacology, Peptide Fragments chemistry, Peptide YY chemistry, Receptors, Neuropeptide Y agonists
- Abstract
Purpose: The anorectic effect of PYY
3-36 makes it a potential pharmacological weight loss treatment. Modifications of the endogenous peptide to obtain commercially attractive pharmacological and biophysical stability properties are examined., Methods: Half-life extended PYY3-36 analogues were prepared and examined regarding Y2 -receptor potency as well as biophysical and stability properties., Results: Deamidation of asparagine in position 18 and 29 was observed upon incubation at 37°C. Asparagine in position 18 - but not position 29 - could be substituted to glutamine without detrimental effects on Y2 -receptor potency. Covalent dimers were formed via the phenol impurity benzoquinone reacting with two N-terminal residues (Isoleucine-Lysine). Both residues had to be modified to suppress dimerization, which could be done without negatively affecting Y2 -receptor potency or other stability/biophysical properties. Introduction of half-life extending modifications in position 30 and 35 eliminated aggregation at 37°C without negatively affecting other stability properties. Placement of a protracting moiety (fatty acid) in the receptor-binding C-terminal region reduced Y2 -receptor potency substantially, whereas only minor effects of protractor position were observed on structural, biophysical or stability properties. Lipidated PYY3-36 analogues formed oligomers of various sizes depending on primary structure and solution conditions., Conclusions: By rational design, a chemically and physically stable Y2 -receptor selective, half-life extended PYY3-36 peptide has been developed., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2021
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