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.