Identification of Compounds Targeting HuD. Another Brick in the Wall of Neurodegenerative Disease Treatment

Ambrosio, F.A., Coricello, A., Costa, G., Lupia, A., Micaelli, M., Marchesi, N., Sala, F., Pascale, A., Rossi, D., Vasile, F., Alcaro, S., Collina, S.

Journal of Medicinal Chemistry, 64 (14), 2021. DOI: 10.1021/acs.jmedchem.1c00191

ABSTRACT. ELAV-like (ELAVL) RNA-binding proteins play a pivotal role in post-transcriptional processes, and their dysregulation is involved in several pathologies. This work was focused on HuD (ELAVL4), which is specifically expressed in nervous tissues, and involved in differentiation and synaptic plasticity mechanisms. HuD represents a new, albeit unexplored, candidate target for the treatment of several relevant neurodegenerative diseases. The aim of this pioneering work was the identification of new molecules able to recognize and bind HuD, thus interfering with its activity. We combined virtual screening, molecular dynamics (MD), and STD-NMR techniques. Starting from around 51 000 compounds, four promising hits eventually provided experimental evidence of their ability to bind HuD. Among the selected best hits, folic acid was found to be the most interesting one, being able to well recognize the HuD binding site. Our results provide a basis for the identification of new HuD interfering compounds which may be useful against neurodegenerative syndromes.