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Synthesis and Characterization of the R27S Genetic Variant of Insulin‐like Peptide 5
Author(s) -
Zaykov Alexander N.,
Gelfanov Vasily M.,
Liu Fa,
DiMarchi Richard D.
Publication year - 2018
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.201800057
Subject(s) - peptide , in vitro , disulfide bond , mutation , population , receptor , chemistry , biochemistry , biology , intramolecular force , phenotype , insulin , combinatorial chemistry , stereochemistry , gene , endocrinology , medicine , environmental health
We report the synthesis and in vitro bioactivity assessment for an insulin‐like peptide 5 (INSL5) analogue that was recently discovered as a genetic mutation in an Amish population. The mutation was associated with improved metabolic status, and receptor‐based antagonism was proposed as a potential mechanism for the altered phenotype. We determined the specific peptide analogue to be fully potent and of maximal efficacy at the human relaxin family peptide receptor 4 (RXFP4), suggesting an alternative basis for the observed effect. In preparation of this synthetically challenging hormone, we have introduced several improvements such as implementation of isoacyl chemistry for high‐efficiency preparation of INSL5 B‐chain and selective intramolecular A6‐11 disulfide formation as a first step in sequential disulfide assembly.