Developing an oxytocin receptor agonist: toward a preclinical candidate for the treatment of autism and social interaction disorders – OT-ism

The objective of this project is to rationally design a preclinical candidate optimized for the treatment of autism spectrum disorder (ASD). ASD is a complex neurodevelopmental disorder diagnosed in presence of primary symptoms, namely impaired social communication and interaction together with a restricted, repetitive repertoire of behaviors (American Psychiatric Association, 2013).
Numerous publications in animals and humans validate the oxytocin (OT) receptor (OTR) as a therapeutic target to develop a treatment for social interaction deficits in ASD. We have already developed and published the first non-peptide agonists of this receptor, active in a mouse model of the pathology. Second generation agonists, more powerful than OT itself in ASD models, have been discovered and patented. They are potent, safe and specific with the exception of agonist activity on the very proximate arginine-vasopressin (AVP) V2 receptor (V2R), leading to an unwanted antidiuretic activity.
Our specific goal is to use cryo-electron microscopy (cryo-EM) structures of both receptors in their active state to rationally design a third generation of OTR agonists devoid of V2R-associated side effects as good preclinical candidates for the treatment of ASD.
This project brings together three teams with very complementary skills who have already contributed to the first phases of the project with synergy and efficiency.
It fits perfectly into one of the seven strategic priorities defined by the French government for this call for projects, namely Autism within neurodevelopmental disorders.