Design of Y-2 Receptor Selective and Proteolytically Stable PYY3-36 Analogues

In recent years peptide YY (PYY) has attracted attention within the area of diabetes and obesity due to its involvement in food intake regulation and glucose homeostasis. It is well-known that PYY1-36 is rapidly cleaved by dipeptidyl peptidase-4 to the more Y2 receptor selective analogue PYY3-36, wh...

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Published inJournal of medicinal chemistry Vol. 61; no. 23; pp. 10519 - 10530
Main Authors Ostergaard, Soren, Kofoed, Jacob, Paulsson, Johan F., Madsen, Kim Grimstrup, Jorgensen, Rasmus, Wulff, Birgitte S.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 13.12.2018
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
POTENT
GLUCAGON-LIKE PEPTIDE-1
METABOLISM
VERSATILE
NPY
IN-VIVO
IDENTIFICATION
BACKBONE
BINDING
NEUROPEPTIDE-Y ANALOGS
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Summary:In recent years peptide YY (PYY) has attracted attention within the area of diabetes and obesity due to its involvement in food intake regulation and glucose homeostasis. It is well-known that PYY1-36 is rapidly cleaved by dipeptidyl peptidase-4 to the more Y2 receptor selective analogue PYY3-36, which is further cleaved to the inactive analogue PYY3-34. In order to improve the selectivity and proteolytic stability of the C-terminus, we synthesized several analogues incorporating N-methyl amino acids or beta-homo amino acids and other non-natural amino acids. These were tested against all four NPY receptors, and highly potent and Y-2 receptor selective analogues were identified by combining a tryptophan residue in position 30 with either N-methyl or beta-homo arginine in position 35. We also identified an analogue with a MeGln(34) substitution that surprisingly displayed high affinity toward all four receptors. In addition, these analogues displayed improved stability toward C-terminal proteolysis compared to native PYY3-36.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b01046