期刊
CHEMMEDCHEM
卷 8, 期 9, 页码 1505-1513出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201300290
关键词
peptide modifications; peptideYY; protein ligation; solid-phase peptide synthesis; structure-activity relationships
资金
- Danish Agency for Science, Technology and Innovation (Ministry of Science, Innovation and Higher Education)
The gut hormone peptideYY (PYY) is postprandially secreted from enteroendocrine Lcells 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 alpha-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.
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