학술논문
Rational Development of Stable PYY.sub.3-36 Peptide Y.sub.2 Receptor Agonists
Research Paper
Research Paper
Document Type
Academic Journal
Author
Source
Pharmaceutical Research. August 2021, Vol. 38 Issue 8, p1369, 17 p.
Subject
Language
English
ISSN
0724-8741
Abstract
Author(s): Christian Poulsen [sup.1], Marie Østergaard Pedersen [sup.1], Per-Olof Wahlund [sup.1], Annika Sjölander [sup.1], Jens Kaalby Thomsen [sup.2], Kilian W. Conde-Frieboes [sup.1], Johan F Paulsson [sup.3], Birgitte S Wulff [sup.3], [...]
Purpose The anorectic effect of PYY.sub.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 PYY.sub.3-36 analogues were prepared and examined regarding Y.sub.2-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.sub.2-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.sub.2-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.sub.2-receptor potency substantially, whereas only minor effects of protractor position were observed on structural, biophysical or stability properties. Lipidated PYY.sub.3-36 analogues formed oligomers of various sizes depending on primary structure and solution conditions. Conclusions By rational design, a chemically and physically stable Y.sub.2-receptor selective, half-life extended PYY.sub.3-36 peptide has been developed.
Purpose The anorectic effect of PYY.sub.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 PYY.sub.3-36 analogues were prepared and examined regarding Y.sub.2-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.sub.2-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.sub.2-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.sub.2-receptor potency substantially, whereas only minor effects of protractor position were observed on structural, biophysical or stability properties. Lipidated PYY.sub.3-36 analogues formed oligomers of various sizes depending on primary structure and solution conditions. Conclusions By rational design, a chemically and physically stable Y.sub.2-receptor selective, half-life extended PYY.sub.3-36 peptide has been developed.