Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington's disease treatment

Sci Rep. 2019 May 13;9(1):7260. doi: 10.1038/s41598-019-43677-7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Disease Models, Animal
  • Drug Design
  • Humans
  • Huntington Disease / drug therapy*
  • Kv Channel-Interacting Proteins / antagonists & inhibitors
  • Kv Channel-Interacting Proteins / drug effects*
  • Mice
  • Neuroprotective Agents / therapeutic use*
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / drug effects*
  • Structure-Activity Relationship

Substances

  • KCNIP3 protein, human
  • Kv Channel-Interacting Proteins
  • Neuroprotective Agents
  • Repressor Proteins