Dimerization (Note: a combination of two identical or different molecules) of the human neuropeptides oxytocin and vasopressin can produce new types of bioactive molecules.
In a recent study, an international research team led by MedUni Vienna and the University of Vienna showed that reduced and therefore much higher levels of oxytocin and vasopressin are still able to activate their receptors. Such a new build offers several opportunities to increase the efficacy of these neuropeptides for therapeutic application.
The researchers were inspired for this approach by naturally occurring dimers. The results have been published in the journal “Chemical Science“.
Oxytocin / vasopressin receptors are typical examples of so-called G protein receptors – the most successful drug target class. The oxytocin and vasopressin receptors are targeted, for example, at childbirth to induce contractions but are also being studied for therapeutic applications in cardiovascular disease, cancer, and developmental disorders such as autism.
Inspired by locusts
MedUni Vienna researchers (led by Christian Gruber from the Institute of Pharmacology), researchers from the University of Vienna (led by Markus Muttenthaler from the Faculty of Chemistry Biological Chemistry) and research partners from Australia and Spain has been shown to be able to reduce the human neuropeptides oxytocin and vasopressin without losing too much of their effectiveness.
The researchers were stimulated by a naturally occurring locust neuropeptide, which had a dimer form of two vasopressin-like molecules. “By making structural changes to the composition and direction of the dimers, we were able to modify their pharmacological activity to inhibit or selectively activate the human vasopressin V1a receptor,” explained Christian Gruber of MedUni Vienna.
Dimerization is the strategy that is often seen in Nature to optimize the stability or mode of action. A good example of this is insulin, which is also a degradation of two different peptides. “
Markus Muttenthaler, Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna
600 million year old oxytocin-vasopressin signaling system
The researchers use a unique strategy to detect new oxytocin and vasopressin molecules with different pharmacological properties, taking advantage of the similar benefits to the evolution of the signaling system. oxytocin-vasopressin which has been around for about 600 million years and is widely distributed in the animal kingdom.
These new pharmacological probes provide new insights into receptor activity and may also represent new therapeutic directions for a number of disorders. “Our concept is as innovative as it is interesting: you take an insect neuropeptide, study its structure and repeat this with small chemical changes to get therapeutic directions for human diseases,” he explained. Gruber and Muttenthaler. “It is equally important to present these new molecules as research ‘tools’. It is only by developing receptor-subtype-selective molecules, that it is possible to study the physiological relevance of these signaling systems,” “add Gruber and Muttenthaler.
The functions of the oxytocin-vasopressin signaling system were studied
The aim of the researchers is to explain the pharmacological and psychological appropriateness of this symptomatic system. “We studied the functioning of this signaling system in ants and found that the hormone system oxytocin-vasopressin regulates excretion, physical activity and metabolism.” So the researchers assume to which oxytocin is not just a ‘love hormone’ but could also be an appetite suppressant – a claim worth exploring.
Source:
Vienna Medical University
Magazine Reference:
Dekan, Z., et al. (2021) Nature-induced reduction as a strategy to modify neuropeptide medication with examples of vasopressin and oxytocin. Chemical science. doi.org/10.1039/D0SC05501H.