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Rational Development of Stable PYY3–36 Peptide Y2 Receptor Agonists.
- Source :
- Pharmaceutical Research; Aug2021, Vol. 38 Issue 8, p1369-1385, 17p
- Publication Year :
- 2021
-
Abstract
- Purpose: The anorectic effect of PYY<subscript>3–36</subscript> 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 PYY<subscript>3–36</subscript> analogues were prepared and examined regarding Y<subscript>2</subscript>-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 Y<subscript>2</subscript>-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 Y<subscript>2</subscript>-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 Y<subscript>2</subscript>-receptor potency substantially, whereas only minor effects of protractor position were observed on structural, biophysical or stability properties. Lipidated PYY<subscript>3–36</subscript> analogues formed oligomers of various sizes depending on primary structure and solution conditions. Conclusions: By rational design, a chemically and physically stable Y<subscript>2</subscript>-receptor selective, half-life extended PYY<subscript>3–36</subscript> peptide has been developed. [ABSTRACT FROM AUTHOR]
- Subjects :
- PEPTIDE receptors
N-terminal residues
ASPARAGINE
DIMERS
BENZOQUINONES
Subjects
Details
- Language :
- English
- ISSN :
- 07248741
- Volume :
- 38
- Issue :
- 8
- Database :
- Complementary Index
- Journal :
- Pharmaceutical Research
- Publication Type :
- Academic Journal
- Accession number :
- 152896376
- Full Text :
- https://doi.org/10.1007/s11095-021-03077-x