6epa

Publication Abstract from PubMed

Protein-protein interactions (PPIs) are known to play an essential role between the neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor Ric8a to regulate synapse function, emerging as a druggable interface for synaptopathies such as the fragile X syndrome (FXS). Recently, the phenothiazine FD44 has been identified as an inhibitor of this PPI, decreasing the abnormally high synapse number and enhancing associative learning in a FXS animal model. Here, we have integrated advanced experimental and computational studies to obtain important structural insights into Drosophila NCS-1/FD44 recognition to understand the basis of its affinity and specificity and generate improved PPI regulators. This has allowed the identification of a new small drug-like molecule, IGS-1.76, which efficiently inhibits the human NCS-1/Ric8a complex with improved binding potency. The crystal structure of the Drosophila NCS-1/IGS-1.76 complex demonstrates that the new inhibitor, although chemically different from FD44, shares the same mechanism of action and constitutes a new hit candidate for FXS.

Deciphering the Inhibition of the Neuronal Calcium Sensor 1 and the Guanine Exchange Factor Ric8a with a Small Phenothiazine Molecule for the Rational Generation of Therapeutic Synapse Function Regulators.,Roca C, Martinez-Gonzalez L, Daniel-Mozo M, Sastre J, Infantes L, Mansilla A, Chaves-Sanjuan A, Gonzalez-Rubio JM, Gil C, Canada FJ, Martinez A, Sanchez-Barrena MJ, Campillo NE J Med Chem. 2018 Jul 26;61(14):5910-5921. doi: 10.1021/acs.jmedchem.8b00088. Epub, 2018 Jul 17. PMID:29966094^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.