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

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

Publication date: May 13, 2019

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.

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Lopez-Hurtado, Alejandro, Peraza, Diego A.., Cercos, Pilar, Lagartera, Laura, Gonzalez, Paz, Dopazo, Xose M.., Herranz, Rosario, Gonzalez, Teresa, Martin-Martinez, Mercedes, Mellstr”om, Britt, Naranjo, Jose R.., Valenzuela, Carmen, and Gutierrez-Rodriguez, Marta. Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington’s disease treatment. 06485. 2019 Sci Rep (9):1.

Concepts Keywords
Binding Site Neuronal calcium sensor
Blockade Drug design
Ca2+ Neuroprotection
DREAM Meglitinide
Drug Design
Homeostasis
Ligand
Modulation
Neuroprotective
Protein
Sci
Vivo

Semantics

Type Source Name
disease MESH weaning
gene UNIPROT HPRT1
gene UNIPROT MYC
drug DRUGBANK Myricetin
gene UNIPROT FBLIM1
disease MESH development
disease MESH fatal outcome
drug DRUGBANK D-glucose
drug DRUGBANK Dextrose unspecified form
gene UNIPROT THOP1
gene UNIPROT FHL5
gene UNIPROT POTEM
gene UNIPROT ACTG1
gene UNIPROT SERPINA3
gene UNIPROT ACTBL2
gene UNIPROT ACTG2
gene UNIPROT ACOT7
gene UNIPROT SYNM
gene UNIPROT FYN
gene UNIPROT DYRK3
gene UNIPROT IK
gene UNIPROT FASTK
gene UNIPROT GDF10
gene UNIPROT HSPA5
gene UNIPROT XBP1
gene UNIPROT ASIC5
gene UNIPROT SSRP1
gene UNIPROT SLC35G1
disease MESH repression
gene UNIPROT RBM8A
drug DRUGBANK Albendazole
gene UNIPROT NR1H4
gene UNIPROT ADRB2
gene UNIPROT BFAR
drug DRUGBANK Dimethyl sulfoxide
gene UNIPROT OCA2
gene UNIPROT B3GALNT1
drug DRUGBANK Proline
disease MESH ***p
gene UNIPROT NOVA2
drug DRUGBANK Amino acids
gene UNIPROT MAGEE1
drug DRUGBANK Hydrogen peroxide
disease DOID neuroblastoma
disease MESH neuroblastoma
drug DRUGBANK Alpha-Linolenic Acid
gene UNIPROT TYR
drug DRUGBANK L-Tyrosine
drug DRUGBANK Glyburide
drug DRUGBANK Water
drug DRUGBANK Magnesium cation
gene UNIPROT FAM107B
gene UNIPROT LARGE1
disease MESH visual
gene UNIPROT AICDA
gene UNIPROT CLDN10
gene UNIPROT KCNIP1
gene UNIPROT RAB35
gene UNIPROT SH3YL1
gene UNIPROT SPR
gene UNIPROT TACR1
drug DRUGBANK Urea
pathway BSID Oxidative Stress
disease MESH oxidative stress
gene UNIPROT SPEF1
gene UNIPROT PDZK1
gene UNIPROT DNMT1
gene UNIPROT CD69
gene UNIPROT CD5L
gene UNIPROT TNFSF13
gene UNIPROT ANP32B
gene UNIPROT PPP3R1
pathway BSID Neurodegenerative Diseases
pathway BSID Insulin secretion
gene UNIPROT SMIM10L2A
gene UNIPROT SMIM10L2B
gene UNIPROT DEPP1
gene UNIPROT GOPC
drug DRUGBANK Arachidonic Acid
gene UNIPROT CA2
drug DRUGBANK Potassium cation
gene UNIPROT KCNC1
disease MESH cognitive impairment
disease MESH choreic movements
gene UNIPROT HTT
disease MESH neurodegenerative disorder
gene UNIPROT CLEC2A
gene UNIPROT BCL10
drug DRUGBANK Coenzyme M
gene UNIPROT ATF6
gene UNIPROT KCND3
pathway BSID Gene Expression
gene UNIPROT FOS
drug DRUGBANK Repaglinide
disease MESH multiple
gene UNIPROT KCNIP3
drug DRUGBANK Calcium

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