Dimerized Neuropeptide Discovery inspired by Nature

In a recent study led by MedUni Vienna and the University of Vienna, researchers demonstrated that dimerized (a combination of two identical or different molecules) and therefore significantly larger versions of human neuropeptides oxytocin and vasopressin are still able to activate their receptors without forfeiting too much of their efficacy. Such new constructs provide several opportunities to optimise the efficacy of these neuropeptides for therapeutic application.

Oxytocin/vasopressin receptors are typical examples of so-called G protein-coupled receptors – the most successful drug target class, which are being investigated for therapeutic applications in cardiovascular disease, cancer and developmental disorders such as autism.

Researchers led by Christian Gruber from the Institute of Pharmacology MeUni Vienna and Markus Muttenthaler from the Institute of Biological Chemistry of the Faculty of Chemistry, University of Vienna, along with research partners from Australia and Spain, were inspired by a naturally occurring locust neuropeptide which had the form of a dimer of two vasopressin-like molecules. "By making structural changes to the composition and orientation of the dimers, we managed to modify their pharmacological activity to achieve selective inhibition or activation of the human vasopressin V1a receptor," explained Christian Gruber from MedUni Vienna. Markus Muttenthaler from the University of Vienna added: "Dimerization is a strategy that is often observed in Nature to optimise stability or mode of action. A good example of this is insulin, which is also a dimer of two different peptides."

"Our concept is as innovative as it is fascinating: you take an insect neuropeptide, study its structure and replicate this with minor chemical changes to obtain therapeutic leads for human diseases. It is equally important to make these new molecules available as research 'tools'. Only by developing receptor-subtype-selective molecules, is it possible to investigate the physiological relevance of these signalling systems," added Gruber and Muttenthaler. "We have studied the function of this signalling system in ants and found that the oxytocin-vasopressin hormone system regulates foraging, physical activity and metabolism."

The researchers also therefore assume that oxytocin is not merely a 'love hormone' but potentially also acts as an appetite suppressant - an application worth investigating, the report suggests.

'Nature-inspired dimerization as a strategy to modulate neuropeptide pharmacology exemplified with vasopressin and oxytocin.' Zoltan Dekan#, Thomas Kremsmayr#, Peter Keov, Mathilde Godin, Ngari Teakle, Leopold Dürrauer, Huang Xiang, Dalia Gharib, Christian Bergmayr, Roland Hellinger, Marina Gay, Marta Vilaseca, Dennis Kurzbach, Fernando Albericio, Paul F Alewood, Christian W Gruber*, Markus Muttenthaler* (#contributed equally, *corresponding authors). Chemical Science, 2021, DOI: 10.1039/D0SC05501H