Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington's disease treatment
DREAM, a neuronal calcium sensor protein, has multiple cellular roles including the regulation of Ca2+ and protein homeostasis. We recently showed that reduced DREAM expression or blockade of DREAM activity by repaglinide is neuroprotective in Huntington's disease (HD). Here we used structure-based drug design to guide the identification of IQM-PC330, which was more potent and had longer lasting effects than repaglinide to inhibit DREAM in cellular and in vivo HD models. We disclosed and validated an unexplored ligand binding site, showing Tyr118 and Tyr130 as critical residues for binding and modulation of DREAM activity. IQM-PC330 binding de-repressed c-fos gene expression, silenced the DREAM effect on KV4.3 channel gating and blocked the ATF6/DREAM interaction. Our results validate DREAM as a valuable target and propose more effective molecules for HD treatment. ; PC was the recipient of a postgraduate FPI fellowship from the Spanish Ministry de Economy, Industry and Competitivity (MINECO). P.C. also thanks the Spanish Society of Therapeutic Chemistry (SEQT) for a Jassen-Cilag Award for young researchers (XVIII Edition, 2016). T.G. holds a Ramón y Cajal contract. D.A.P. holds a CSIC contract. This work was funded by the Spanish Ministery of Economy, Industry and Competitivity (AEI-FEDER, EU grants): BFU2015-67284-R (to M.G.R., R.H.), SAF2017-89554-R (to J.R.N.), SAF2016-75021-R (to C.V.) and SAF2015-66275-C2-2-R (to M.M.M.); the Instituto de Salud Carlos III CIBERNED and CIBERCV programs (to J.R.N. and to C.V., respectively) and the Madrid regional government/Neurodegmodels (to J.R.N.); CSIC grant PIE201880E109 (to M.G.R., R.H. and M.M.M.) and PIE201820E104 (to C.V.). ; Peer reviewed
