Highly Potent Peptide Therapeutics To Prevent Protein Aggregation in Huntington’s Disease

Khan A., Özçelik C. E., Begli O., Oguz O., KESİCİ M. S., Kasırga T. S., ...More

ACS Medicinal Chemistry Letters, vol.14, no.12, pp.1821-1826, 2023 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 14 Issue: 12
  • Publication Date: 2023
  • Doi Number: 10.1021/acsmedchemlett.3c00415
  • Journal Name: ACS Medicinal Chemistry Letters
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, EMBASE
  • Page Numbers: pp.1821-1826
  • Keywords: Htt aggregation, Huntingtin, Huntington’s Disease, Inhibition, Peptide-based drug therapy
  • Yıldız Technical University Affiliated: Yes


Huntington’s disease (HD) is a neurodegenerative disorder resulting from a significant amplification of CAG repeats in exon 1 of the Huntingtin (Htt) gene. More than 36 CAG repeats result in the formation of a mutant Htt (mHtt) protein. These amino-terminal mHtt fragments lead to the formation of misfolded proteins, which then form aggregates in the relevant brain regions. Therapies that can delay the progression of the disease are imperative to halting the course of the disease. Peptide-based drug therapies provide such a platform. Inhibitory peptides were screened against monomeric units of both wild type (Htt(Q25)) and mHtt fragments, Htt(Q46) and Htt(Q103). Fibril kinetics was studied by utilizing the Thioflavin T (ThT) assay. Atomic force microscopy was also used to study the influence of the peptides on fibril formation. These experiments demonstrate that the chosen peptides suppress the formation of fibrils in mHtt proteins and can provide a therapeutic lead for further optimization and development.