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

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 mi...

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Published inACS medicinal chemistry letters Vol. 14; no. 12; pp. 1821 - 1826
Main Authors Khan, Anooshay, Özçelik, Cemile Elif, Begli, Ozge, Oguz, Oguzhan, Kesici, Mehmet Seçkin, Kasırga, Talip Serkan, Özçubukcu, Salih, Yuca, Esra, Seker, Urartu Ozgur Safak
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 14.12.2023
Subjects
Huntington’s Disease
Peptide-based drug therapy
Htt aggregation
Inhibition
Huntingtin
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Abstract 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.
AbstractList 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.
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.
Author Özçelik, Cemile Elif
Yuca, Esra
Khan, Anooshay
Özçubukcu, Salih
Oguz, Oguzhan
Kesici, Mehmet Seçkin
Begli, Ozge
Kasırga, Talip Serkan
Seker, Urartu Ozgur Safak
AuthorAffiliation Department of Chemistry, Faculty of Science
Yildiz Technical University
Department of Molecular Biology and Genetics
Middle East Technical University
UNAM-Institute of Materials Science and Nanotechnology
Health Biotechnology Joint Research and Application Center of Excellence
Bilkent University
Department of Neurosciences
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Keywords Huntington’s Disease
Peptide-based drug therapy
Htt aggregation
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Huntingtin
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Snippet Huntington’s disease (HD) is a neurodegenerative disorder resulting from a significant amplification of CAG repeats in exon 1 of the Huntingtin (Htt) gene....
Huntington's disease (HD) is a neurodegenerative disorder resulting from a significant amplification of CAG repeats in exon 1 of the Huntingtin (Htt) gene....
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Title Highly Potent Peptide Therapeutics To Prevent Protein Aggregation in Huntington’s Disease
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