Biocompatible inhibitor based on chitosan and amphiphilic peptide against mutant Huntingtin toxicity.

Biocompatible inhibitor based on chitosan and amphiphilic peptide against mutant Huntingtin toxicity.

Publication date: Jun 05, 2019

Huntington’s disease (HD) is classified as protein-misfolding diseases correlated with the mutant Huntingtin (mHtt) protein with abnormally expanded polyglutamine (polyQ) domains. Since no effective drug is reported until now, attempts to develop a better therapy to delay the age of onset become an urgent demand. In this study, an amphiphilic peptide consisting of negatively charged hexa-glutamic acid and a stretch of deca-glutamine (E₆Q₁₀) was chemically synthesized as an inhibitor against polyQ and mHtt toxicity. We found E₆Q₁₀ self-assembled into spherical vesicles as shown by TEM, cryo-EM and dynamic light scattering. The assembled E₆Q₁₀ prevented polyQ-rich peptide (KKWQ₂₀AKK) from forming amyloid fibrils. To enable the cell-penetration ability of E₆Q₁₀, we generated the E₆Q₁₀-chitosan complex. We demonstrate the complex penetrate cells, interfere with the mHtt oligomerization and aggregation process, and prevent mHtt cytotoxicity. By combining positively charged chitosan and amphiphilic peptides with negatively charge moiety, we provided a new strategy to develop biocompatible and biodegradable inhibitor against mHtt toxicity.

Wahyuningtyas, D., Chen, W.H., Huang, C.H., He, Y.J., and Huang, J.J. Biocompatible inhibitor based on chitosan and amphiphilic peptide against mutant Huntingtin toxicity. 06515. 2019 Chembiochem.

Concepts Keywords
Amphiphilic Proteopathy
Amyloid Trinucleotide repeat disorder
Biocompatible PolyQ
Biodegradable Amyloid
Chitosan Chitosan
Cytotoxicity Amphiphile
Dynamic Light Scattering Huntingtin
Fibrils Huntington’s disease
Glutamic Acid Neurological disorders
Glutamine Branches of biology
Huntingtin
Huntington
Inhibitor
Moiety
Mutant
Oligomerization
Peptide
Peptides
PolyQ
Protein Misfolding
TEM
Toxicity
Vesicles

Semantics

Type Source Name
drug DRUGBANK Tretamine
gene UNIPROT CYLD
gene UNIPROT TNMD
gene UNIPROT TNFSF14
drug DRUGBANK L-Glutamine
gene UNIPROT HEXA
drug DRUGBANK Glutamic Acid
drug DRUGBANK Tropicamide

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