Potential entry points for Huntington’s disease drug discovery

Potential entry points for Huntington’s disease drug discovery

Publication date: Nov 01, 2019

The team carried out a smartly designed screening featuring a small-molecule microarray and front-edge optical technologies, and managed to identify four small molecule compounds that specifically reduced the protein that causes Huntington’s disease.

“Small molecule glue” helps autophagosomes “engulf” the disease-causing protein Since the conventional approach is infeasible for mHTT, the team came up with a fundamentally new idea, which was to degrade mHTT by harnessing autophagy, an intracellular protein degradation process.

To identify compounds that only degrade mHTT but not wild-type HTT, the team envisioned a “small molecule glue” functioning as an “autophagosome tethering compound” (ATTEC), which could tether LC3 and mHTT together so that mHTT is engulfed into autophagosomes for degradation.

The team found that these four compounds significantly reduced mHTT levels in HD mouse neurons, HD patient cells, and HD drosophila models at ~10 to 100 nanomolar concentrations, with little effect on wild-type HTT levels.

Using this cutting-edge screening approach, the team found two small molecules that could bind to both LC3 and mHTT proteins, but not to wild-type HTT.

Autophagosome tethering compounds may open new windows for drug discovery The team further explored the intrinsic mechanisms by which these small molecule compounds could distinguish between mutant and wild-type HTT proteins, which were almost identical except in the glutamine repeat (polyQ) length.

Based on this, the team realized that the application of these small molecule compounds may reach far beyond the potential treatment of Huntington’s disease.

With SCA3 patient cells provided by Dr. Yimin Sun from Prof. Jian Wang’s group at Huashan Hospital affiliated to Fudan University, the team found that these compounds could effectively reduce the level of the mutant ATXN3 protein (with a polyQ length of 74) that causes the disease, without affecting the wild-type ATXN3 (with a polyQ length of 27).

The new concept of drug development using autophagosome-binding compounds (ATTEC) may also be applied to other pathogenic proteins that are undruggable, or even to pathogenic substances that are not proteins, such as organelles or lipids. “

Concepts Keywords
Allele DNA Chip
Autophagy Drug discovery
Bioactivity PolyQ
Biochemical Trinucleotide repeat disorder
Blood Brain Barrier Neurodegeneration
Chinese Huntingtin
Chorea Autophagy
Cognitive Autophagosome
Cortex Vesicles
Cross Huntington’s disease
Drosophila Cell biology
Drug Discovery Branches of biology
Exophthalmos Pathogenic treat disease
Facial Muscle Deficiency
Fair Dealing Disease diseases
Fudan University Applicable polyQ diseases
Glutamine Exophthalmos hyperreflexia
Huntingtin PolyQ diseases
Huntington
Hyperreflexia
Incidence
Informatics Engineering
Interact
Intracellular
Intraperitoneal Injection
Light Reflection
Linker
Lipids
Lysosomes
Mice
Microarray
Molecular Layer
Mutant
Nanomolar
Nature
Neurodegenerative Diseases
Neurons
Neuroprotection
Organelles
Pathogenic
Phenotypes
PolyQ
Protein
Reflectivity
Small Molecule
Spinocerebellar Ataxia
Striatum
Tendon
Tether
Tethering
Throughput
Wild Type

Semantics

Type Source Name
disease MESH hyperreflexia
disease DOID exophthalmos
drug DRUGBANK Isoxaflutole
disease MESH exophthalmos
disease MESH posture
gene UNIPROT ATXN3
disease DOID spinocerebellar ataxia
disease MESH development
gene UNIPROT STUB1
gene UNIPROT TNFSF14
drug DRUGBANK L-Glutamine
gene UNIPROT SLC6A4
gene UNIPROT HTT
disease MESH abnormalities
gene UNIPROT WDFY2
gene UNIPROT RNF2
disease MESH neurodegenerative diseases
pathway BSID Neurodegenerative Diseases
disease MESH chorea
disease DOID chorea

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