GNAO1 encephalopathy therapy: from thousands of candidates to one
Pediatric GNAO1 encephalopathies are rare but severe brain disease causing epilepsy, movement disorders, and developmental delays. It stems from mutations in a single gene encoding a key brain protein called Gαo.
A protein stuck in the "on" position
In healthy brain cells, the Gαo protein acts like a molecular switch: it turns on briefly to transmit signals, then turns off again. In 2022, researchers from Prof. Vladimir Katanaev's laboratory discovered that one of the most common mutations causing GNAO1 encephalopathy turns the switch in the "on" position permanently. This causes seizures, movement problems, and developmental delays. Finding a drug able to restore the switch could open new perspectives for patients.
54,080 compounds screened, one promising hit
To find a chemical capable of correcting this overactivation, the team tested a huge library of 54,080 chemical compounds. The experiments measuring how the mutant Gαo protein behaves were carried out with the support of the READS facility, whose technical expertise was key to running the screen at this scale.
Only one compound stood out. This small molecule turns off the Gαo protein, and does so with greater effect on the defective mutant form than on the healthy one, an encouraging sign for future safety.
Among 54,080 compounds, only one small molecule is able to restore the proper function of the mutant Gαo protein. Adapted from Figure 2 in Larasati et al. 2026
A starting point, not yet a medicine
This compound is not a drug ready for patients. It is a promising molecular scaffold, that now needs to be refined and optimised before it could ever reach the clinic. But it is proof that the defect can be pharmacologically restored, something that was never done before.