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A Parallel Semisynthetic Approach for Structure–Activity Relationship Studies of Peptide YY
Author(s) -
Albertsen Louise,
Østergaard Søren,
Paulsson Johan F.,
Norrild Jens Chr.,
Strømgaard Kristian
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300290
Subject(s) - peptide yy , tetrapeptide , chemistry , peptide , energy homeostasis , receptor , anorectic , stereochemistry , biochemistry , endocrinology , medicine , neuropeptide y receptor , biology , neuropeptide , food intake
The gut hormone peptide YY (PYY) is postprandially secreted from enteroendocrine L cells and is involved in the regulation of energy homeostasis. The N‐terminal truncated version PYY(3–36) decreases food intake and has potential as an anti‐obesity agent. The anorectic effect of PYY(3–36) is mediated through Y 2 receptors in the hypothalamus, vagus, and brainstem regions, and it is well known that the C‐terminal tetrapeptide sequence of PYY(3–36) is crucial for Y 2 receptor activation. The aim of this work was to develop a semisynthetic methodology for the generation of a library of C‐terminally modified PYY(3–36) analogues. By using an intein‐based expression system, PYY(3–29) was generated as a C‐terminal peptide α‐thioester. Heptapeptides bearing an N‐terminal cysteine and modifications at one of the four C‐terminal positions were synthesized in a 96‐well plate by parallel solid‐phase synthesis. In the plate format, an array of [Ala30]PYY(3–36) analogues were generated by ligation, desulfurization, and subsequent solid‐phase extraction. The generated analogues, in which either Arg33, Gln34, Arg35, or Tyr36 had been substituted with proteinogenic or non‐proteinogenic amino acids, were tested in a functional Y 2 receptor assay. Generally, substitutions of Tyr36 were better tolerated than modifications of Arg33, Gln34, and Arg35. Two analogues showed significantly improved Y 2 receptor selectivity; therefore, these results could be used to design new drug candidates for the treatment of obesity.