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

Vasopressin (VP) and oxytocin (OT) are cyclic neuropeptides that regulate fundamental physiological functions via four G protein-coupled receptors, V 1a R, V 1b R, V 2 R, and OTR. Ligand development remains challenging for these receptors due to complex structure-activity relationships. Here, we inv...

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Bibliographic Details
Published in:Chemical science (Cambridge) 2021-03, Vol.12 (11), p.457-462
Main Authors: Dekan, Zoltan, Kremsmayr, Thomas, Keov, Peter, Godin, Mathilde, Teakle, Ngari, Dürrauer, Leopold, Xiang, Huang, Gharib, Dalia, Bergmayr, Christian, Hellinger, Roland, Gay, Marina, Vilaseca, Marta, Kurzbach, Dennis, Albericio, Fernando, Alewood, Paul F, Gruber, Christian W, Muttenthaler, Markus
Format: Article
Language:English
Subjects:
Chemistry
Construction
Dimerization
Dimers
Ligands
Mass spectra
Pharmacology
Receptors
Structural analysis
Valine
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Summary:Vasopressin (VP) and oxytocin (OT) are cyclic neuropeptides that regulate fundamental physiological functions via four G protein-coupled receptors, V 1a R, V 1b R, V 2 R, 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 V 1a R. 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. Structural and pharmacological study of parallel, antiparallel and N- to C-terminal cyclized homo- and heterodimers of vasopressin and oxytocin. This study spotlights dimerization as a strategy to modulate the pharmacology of neuropeptides.
ISSN:2041-6520
2041-6539
DOI:10.1039/d0sc05501h