Human Insulin-like Peptide 5 (INSL5). Identification of a Simplified Version of Two-Chain Analog A13.

Abstract

The receptor for insulin-like peptide 5 (INSL5), RXFP4, is a potential pharma target for treating human conditions such as constipation, anorexia, and obesity. However, since INSL5 has a complex structure of two chains and three disulfide bonds, its synthesis has proven to be extremely difficult via either chemical or recombinant approaches. Previous studies led to the engineering of a high yielding simplified INSL5 analog, named analog 13 (A13), which retains native INSL5-like activity. The focus of this study is to further simplify the structure of A13 by truncating the N-terminal residues of the B-chain. We have found that the first six residues at the N-terminus of A13 are not important for RXFP4 binding and cAMP potency. The most minimized active structure of INSL5 identified in this study is A13: B7-24 which will be an important research tool to study the physiological role of RXFP4 and a template for further modification to improve its pharmacokinetic properties.

• Authors: Xiaozhou Zhang, Ross A D Bathgate, Mohammed Akhter Hossain
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 11 Issue 12 Pg. 2455-2460 (Dec 10 2020) ISSN: 1948-5875 [Print] United States
• PMID: 33335667 (Publication Type: Journal Article)
• Copyright: © 2020 American Chemical Society.