Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds

Frontiers in Chemistry

Ross A. D. Bathgate¹  K. Johan Rosengren²  Linda M. Haugaard-Kedström²  Angela Song²  Michael Postan²  Han Siean Lee²  Richard J. Clark² 

[1] Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, VIC, Australia;Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia;Florey Department of Neuroscience and Mental Health, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia;

关键词: relaxin-3;    RXFP3;    grafting;    apamin;    VhTI;    disulfide-scaffold;   

DOI  :  10.3389/fchem.2020.00087

来源: DOAJ

【 摘 要 】

Relaxin-3 is a neuropeptide with important roles in metabolism, arousal, learning and memory. Its cognate receptor is the relaxin family peptide-3 (RXFP3) receptor. Relaxin-3 agonist and antagonist analogs have been shown to be able to modulate food intake in rodent models. The relaxin-3 B-chain is sufficient for receptor interactions, however, in the absence of a structural support, linear relaxin-3 B-chain analogs are rapidly degraded and thus unsuitable as drug leads. In this study, two different disulfide-stabilized scaffolds were used for grafting of important relaxin-3 B-chain residues to improve structure and stability. The use of both Veronica hederifolia Trypsin inhibitor (VhTI) and apamin grafting resulted in agonist and antagonist analogs with improved helicity. VhTI grafted peptides showed poor binding and low potency at RXFP3, on the other hand, apamin variants retained significant activity. These variants also showed improved half-life in serum from ~5 min to >6 h, and thus are promising RXFP3 specific pharmacological tools and drug leads for neuropharmacological diseases.

【 授权许可】

Unknown