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Biocompatible Inhibitor Based on Chitosan and Amphiphilic Peptide against Mutant Huntingtin Toxicity
Author(s) -
Wahyuningtyas Devi,
Chen WenHao,
Huang ChenHan,
He YuJung,
Huang Joseph JenTse
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900242
Subject(s) - huntingtin , amphiphile , peptide , huntingtin protein , biophysics , chemistry , mutant , fibril , cytotoxicity , chitosan , toxicity , biochemistry , biology , in vitro , organic chemistry , copolymer , gene , polymer
Huntington's disease (HD) is classified as a protein‐misfolding disease correlated with the mutant Huntingtin (mHtt) protein with abnormally expanded polyglutamine (polyQ) domains. Because no effective drugs have yet been reported, attempts to develop better therapy to delay the age of onset are in urgent demand. In this study, an amphiphilic peptide consisting of negatively charged hexaglutamic acid and a stretch of decaglutamine (E 6 Q 10 ) was chemically synthesized as an inhibitor against polyQ and mHtt toxicity. It is found that E 6 Q 10 selfassembles into spherical vesicles, as shown by means of TEM, cryoelectron microscopy, and dynamic light scattering. Assembled E 6 Q 10 prevented the polyQ‐rich peptide (KKWQ 20 AKK) from forming amyloid fibrils. To enable the cell‐penetration ability of E 6 Q 10 , the E 6 Q 10 ⋅ chitosan complex was generated. It is demonstrated that the complex penetrates cells, interferes with the mHtt oligomerization and aggregation process, and prevents mHtt cytotoxicity. By combining positively charged chitosan and amphiphilic peptides with a negatively charge moiety, a new strategy is provided to develop biocompatible and biodegradable inhibitors against mHtt toxicity.