Effects of C-Terminal B-Chain Modifications in a Relaxin 3 Agonist Analogue

Praveen Praveen, Julien Tailhades, K. Johan Rosengren, Mengjie Liu, John D. Wade, Ross A.D. Bathgate, Mohammed Akhter Hossain

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

The receptor for the neuropeptide relaxin 3, relaxin family peptide 3 (RXFP3) receptor, is an attractive pharmacological target for the control of eating, addictive, and psychiatric behaviors. Several structure-Activity relationship studies on both human relaxin 3 (containing 3 disulfide bonds) and its analogue A2 (two disulfide bonds) suggest that the C-Terminal carboxylic acid of the tryptophan residue in the B-chain is important for RXFP3 activity. In this study, we have added amide, alcohol, carbamate, and ester functionalities to the C-Terminus of A2 and compared their structures and functions. As expected, the C-Terminal amide form of A2 showed lower binding affinity for RXFP3 while ester and alcohol substitutions also demonstrated lower affinity. However, while these analogues showed slightly lower binding affinity, there was no significant difference in activation of RXFP3 compared to A2 bearing a C-Terminal carboxylic acid, suggesting the binding pocket is able to accommodate additional atoms.

Original languageEnglish
Pages (from-to)2336-2340
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume11
Issue number11
DOIs
Publication statusPublished - 12 Nov 2020

Keywords

  • GPCR
  • H3 relaxin
  • Insulin-like peptide
  • peptidomimetic
  • relaxin 3
  • solid phase peptide synthesis

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