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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<jats:sub>6<\/jats:sub>Q<jats:sub>10<\/jats:sub>) was chemically synthesized as an inhibitor against polyQ and mHtt toxicity. It is found that E<jats:sub>6<\/jats:sub>Q<jats:sub>10<\/jats:sub> selfassembles into spherical vesicles, as shown by means of TEM, cryoelectron microscopy, and dynamic light scattering. Assembled E<jats:sub>6<\/jats:sub>Q<jats:sub>10<\/jats:sub> prevented the polyQ\u2010rich peptide (KKWQ<jats:sub>20<\/jats:sub>AKK) from forming amyloid fibrils. To enable the cell\u2010penetration ability of E<jats:sub>6<\/jats:sub>Q<jats:sub>10<\/jats:sub>, the E<jats:sub>6<\/jats:sub>Q<jats:sub>10<\/jats:sub><jats:bold>\u22c5<\/jats:bold>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.<\/jats:p>","DOI":"10.1002\/cbic.201900242","type":"journal-article","created":{"date-parts":[[2019,6,5]],"date-time":"2019-06-05T07:19:10Z","timestamp":1559719150000},"page":"2133-2140","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Biocompatible Inhibitor Based on Chitosan and Amphiphilic Peptide against Mutant Huntingtin Toxicity"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2979-7466","authenticated-orcid":false,"given":"Devi","family":"Wahyuningtyas","sequence":"first","affiliation":[{"name":"Institute of Chemistry Academia Sinica  No. 128 Sec. 2 Academia Road Nankang Taipei 115 Taiwan"},{"name":"Sustainable Chemical Science and Technology Program Taiwan International 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