ML290 is a biased allosteric agonist at the relaxin receptor RXFP1

Martina Kocan; Mohsin Sarwar; Sheng Y Ang; Jingbo Xiao; Juan J Marugan; Mohammed A Hossain; Chao Wang; Dana S Hutchinson; Chrishan S Samuel; Alexander I Agoulnik; Ross AD Bathgate; Roger J Summers

Journal article

ML290 is a biased allosteric agonist at the relaxin receptor RXFP1

Martina Kocan, Mohsin Sarwar, Sheng Y Ang, Jingbo Xiao, Juan J Marugan, Mohammed A Hossain, Chao Wang, Dana S Hutchinson, Chrishan S Samuel, Alexander I Agoulnik, Ross AD Bathgate, Roger J Summers

SCIENTIFIC REPORTS | NATURE PUBLISHING GROUP | Published : 2017

DOI: 10.1038/s41598-017-02916-5

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Abstract

Activation of the relaxin receptor RXFP1 has been associated with improved survival in acute heart failure. ML290 is a small molecule RXFP1 agonist with simple structure, long half-life and high stability. Here we demonstrate that ML290 is a biased agonist in human cells expressing RXFP1 with long-term beneficial actions on markers of fibrosis in human cardiac fibroblasts (HCFs). ML290 did not directly compete with orthosteric relaxin binding and did not affect binding kinetics, but did increase binding to RXFP1. In HEK-RXFP1 cells, ML290 stimulated cAMP accumulation and p38MAPK phosphorylation but not cGMP accumulation or ERK1/2 phosphorylation although prior addition of ML290 increased p-E..

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University of Melbourne Researchers

Akhter Hossain Author Florey Department of Neuroscience and Mental Health

Chrishan Samuel Author Biochemistry and Pharmacology

Ross Bathgate Author Florey Department of Neuroscience and Mental Health

Martina Kocan Author Biosciences

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RESEARCH FELLOWSHIP

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Awarded by Australian Research Council

Awarded by National Cancer Institute

Awarded by NATIONAL CANCER INSTITUTE

Awarded by NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

Funding Acknowledgements

We thank Sharon Layfield and Tania Ferraro for technical assistance, Dr Melanie White (Australian Institute for Regenerative Medicine, Monash University) for the pENTR L1-R5 Ef1 alpha construct and Prof. Alon Chen (Weizmann Institute of Science, Israel) for the gift of pMDL, pRev and pVSVG plasmids. Research at the Florey was supported by National Health and Medical Research Council of Australia project grants 628427 and 1043750 (RADB) and by the Victorian Government Operational Infrastructure Support Program. CSS 1041766 and RADB 1042650 are NHMRC Senior Research Fellows and DSH 545952 is an NHMRC Career Development Fellow. Research at Drug Discovery Biology, Monash Institute of Pharmaceutical Science was supported by National Health and Medical Research Council Program Grant 1055134 (RJS) and by Australian Research Council Linkage Grant LP110100288 (RJS, RADB, CSS) and Industry Partner Corthera Inc. Research at Florida International University was supported by National Cancer Institute grant U01CA177711 (AIA). (San Mateo, CA) who also supplied H2 relaxin.