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

doi:10.1021/acsmedchemlett.0c00456

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

ACS Med Chem Lett. 2020 Oct 22;11(11):2336-2340. doi: 10.1021/acsmedchemlett.0c00456. eCollection 2020 Nov 12.

Authors

Praveen Praveen¹, Julien Tailhades^{2

3}, K Johan Rosengren⁴, Mengjie Liu¹, John D Wade^{1

5}, Ross A D Bathgate^{1

5}, Mohammed Akhter Hossain^{1

5}

Affiliations

¹ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia.
² The Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
³ EMBL Australia, Monash University, Clayton, Victoria 3800, Australia.
⁴ School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
⁵ School of Chemistry and Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.

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.