Anti-obesity drug development

Sympathetic neurons have a wide range of physiological functions and their hypoactivity contributes to obesity and diabetes, among other syndromes. Sympathomimemic drugs rescue this deficiency but this drug class, mostly composed of brain-penetrant amphetamines and adrenergic agonists, is both cardiotoxic and highly controlled. Our recent publication puts forward new class of drugs  named Sympathofacilitators that do not enter the brain and have an anti-obesity and cardio-neutral effect in vivo. The first-in-class was published in Mahu I et al Domingos, Cell Metabolism 2020; Fig. 3C of this paper demonstrated a neuro-facilitatory effect, rather than neuro-excitatory one. 

This new class is in needed of novel chemical entities which can be screened in vitro on cultured iPSC-derived sympathetic neurones. The screen would be based on fluorescent readouts of calcium activity reporter, screening for a facilitation of responses to acetylcholine (similar to Fig. 3C of Mahu I et al).

The prospect of identifying natural compounds that have a Sympathofacilitatory effect is tangible when performed in collaboration with the laboratory of Barry O’Keefe. The student will learn lab how to grow and scale-up iPSC-derived sympathetic neurones in Domingos lab, and optimize an in vitro assay based on Fig. 3C. The student will then transfer this knowledge to the lab of Barry O’Keefe where the screen will be performed using a fluorescent plate reader, robotic liquid handling, and a library of natural compounds.