Biocompatible Inhibitor Based on Chitosan and Amphiphilic Peptide against Mutant Huntingtin Toxicity

Abstract

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 (E6Q10) was chemically synthesized as an inhibitor against polyQ and mHtt toxicity. It is found that E6Q10 selfassembles into spherical vesicles, as shown by means of TEM, cryoelectron microscopy, and dynamic light scattering. Assembled E6Q10 prevented the polyQ‐rich peptide (KKWQ20AKK) from forming amyloid fibrils. To enable the cell‐penetration ability of E6Q10, the E6Q10⋅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.

Polyglutamine-Specific Gold Nanoparticle Complex Alleviates Mutant Huntingtin-Induced Toxicity

“…Besides, because the treatment of bare AuNPs had neglectable effects on the mHtt inclusion, we surmised that the JLD1 in the complex had a role in preventing the aggregate formation. In the previous study, we had shown that JLD1 alone interrupted the protein aggregation process with its negatively charged sequence through charge repulsion . In this work, we further demonstrated that the incorporation of JLD1 on the surface of AuNPs had a synergetic effect to enhance the disaggregation ability.…”

“…In the previous study, we had shown that JLD1 alone interrupted the protein aggregation process with its negatively charged sequence through charge repulsion. 40 In this work, we further demonstrated that the incorporation of JLD1 on the surface of AuNPs had a synergetic effect to enhance the disaggregation ability. Although the amphiphilic JLD1 provided the electrostatic repulsion, the AuNPs offered a steric hindrance to prevent further aggregation.…”

“…We have earlier demonstrated that deca-glutamine-containing peptides interacted with mHtt. , Herein, we incorporated an amphiphilic peptide (JLD1) composed of a polyglutamine-binding sequence (deca-glutamine), a negatively charged sequence (hexa-glutamic acid), and a linker (cysteine–triglycine) on the surface of AuNPs to mitigate mHtt neurotoxicity and disassemble its aggregation (Figure ). The JLD1 was incorporated on the surface of citrate-stabilized AuNPs through gold–sulfur interaction.…”

Unraveling the Puzzle of Therapeutic Peptides: A Promising Frontier in Huntington’s Disease Treatment

“…Another amphiphilic peptide, E 6 Q 10 , was designed and synthesized using negatively charged hexaglutamic acid (E 6 ) residues and a decaglutamine (Q 10 ) stretch to prevent the aggregation of mHTT and reduce its toxicity in neuronal cells. 83 Figure 16 B illustrates the self-assembly of the amphiphilic E 6 Q 10 into a structure resembling a vesicle. Here, Q 10 recognizes and binds to the mHTT protein, while E 6 enhances solubility, prevents oligomerization, and aids in separating mHTT aggregates through charge repulsion.…”

“…These peptides have been classified into distinct categories based on their specific mechanisms of action. These categories include inhibition of mHTT aggregation (represented by black, blue, and red), − degradation of extended CAG RNA (represented by purple), − and targeting mHTT interaction with InsP3R1 (represented by green), CaM (represented by yellow), − or Caspase-6 (represented by turquoise) . The historical background of HD is displayed in pink.…”