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  3. Nature-inspired dimerization as a strategy to modulate neuropeptide pharmacology exemplified with vasopressin and oxytocin

Nature-inspired dimerization as a strategy to modulate neuropeptide pharmacology exemplified with vasopressin and oxytocin

  • Chem Sci. 2021 Feb 4;12(11):4057-4062. doi: 10.1039/d0sc05501h.
Zoltan Dekan 1,  Thomas Kremsmayr 2,  Peter Keov 3,  Mathilde Godin 1,  Ngari Teakle 1,  Leopold Dürrauer 2,  Huang Xiang 4,  Dalia Gharib 4,  Christian Bergmayr 4,  Roland Hellinger 4,  Marina Gay 5,  Marta Vilaseca 5,  Dennis Kurzbach 2,  Fernando Albericio 6,  Paul F Alewood 1,  Christian W Gruber 3 4,  Markus Muttenthaler 1 2
Affiliations

Affiliations

  • 1 Institute for Molecular Bioscience, The University of Queensland Brisbane 4072 Australia m.muttenthaler@uq.edu.au.
  • 2 Institute of Biological Chemistry, University of Vienna Währingerstraße 38 1090 Vienna Austria markus.muttenthaler@univie.ac.at.
  • 3 Faculty of Medicine, School of Biomedical Sciences, The University of Queensland Brisbane 4072 Australia.
  • 4 Center for Physiology and Pharmacology, Medical University of Vienna Schwarzspanierstraße 17 1090 Vienna Austria christian.w.gruber@meduniwien.ac.at.
  • 5 Institute for Research in Biomedicine Barcelona C/ Baldiri Reixac 10 08028 Barcelona Spain.
  • 6 Department of Organic Chemistry, University of Barcelona Barcelona Science Park, Baldiri Reixac 10 08028 Barcelona Spain.
PMID: 34163676 DOI: 10.1039/d0sc05501h
Abstract

Vasopressin (VP) and oxytocin (OT) are cyclic neuropeptides that regulate fundamental physiological functions via four G protein-coupled receptors, V1aR, V1bR, V2R, and OTR. Ligand development remains challenging for these receptors due to complex structure-activity relationships. Here, we investigated dimerization as a strategy for developing ligands with novel pharmacology. We regioselectively synthesised and systematically studied parallel, antiparallel and N- to C-terminal cyclized homo- and heterodimer constructs of VP, OT and dVDAVP (1-deamino-4-valine-8-d-arginine-VP). All disulfide-linked dimers, except for the head-to-tail cyclized constructs, retained nanomolar potency despite the structural implications of dimerization. Our results support a single chain interaction for receptor activation. Dimer orientation had little impact on activity, except for the dVDAVP homodimers, where an antagonist to agonist switch was observed at the V1aR. This study provides novel insights into the structural requirements of VP/OT receptor activation and spotlights dimerization as a strategy to modulate pharmacology, a concept also frequently observed in nature.

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