Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 12, Pages 2455-2460Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00435
Keywords
INSL5; peptide hormone; gut peptide; RXFP4; structure-activity relationship (SAR) study
Categories
Funding
- NHMRC (Australia) IDEAS grant [APP1182996]
- NHMRC Research Fellowship [1135837]
- Victorian Government's Operational Infrastructure Support Program
- National Health and Medical Research Council of Australia [1135837] Funding Source: NHMRC
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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.
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