Related Experiment Video

Updated: Jun 30, 2026

Peptide-based Identification of Functional Motifs and their Binding Partners
14:28

Peptide-based Identification of Functional Motifs and their Binding Partners

Published on: June 30, 2013

13.1K

High-affinity, structure-validated and selective macrocyclic peptide tools for chemical biology studies of Huntingtin

Rebeka Fanti1,2, Esther Wolf1,3, Tatsuya Ikenoue4

  • 1Structural Genomics Consortium, University Health Network, Toronto, ON M5G 1L7, Canada.

Proceedings of the National Academy of Sciences of the United States of America
|March 16, 2026
PubMed

Insights

Researchers developed new macrocyclic peptide binders targeting the Huntingtin (HTT) protein to study Huntington's disease (HD). These selective chemical tools offer potential for developing novel therapies for this fatal neurodegenerative disorder.

Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • Huntington's disease (HD) is a fatal neurodegenerative disorder.
  • It is caused by a Cytosine-Adenosine-Guanine (CAG) repeat expansion in the Huntingtin (HTT) gene.
  • Currently, no disease-modifying therapies are available for HD, and the HTT protein's function remains unclear due to a lack of selective chemical tools.

Purpose of the Study:

  • To identify and characterize novel chemical tools for studying the Huntingtin (HTT) protein.
  • To develop selective binders for the HTT protein to aid functional studies.

Main Methods:

  • Identification and characterization of macrocyclic peptide binders.
  • In vitro affinity assays.
  • Hydrogen-deuterium exchange mass spectrometry (HDX-MS).
  • Cryoelectron microscopy (cryo-EM).
  • Chemoproteomics.
  • Analysis of HTT-HAP40 complex formation.

Main Results:

  • Novel macrocyclic peptide binders targeting HTT were identified and characterized.
  • These binders exhibit low-nanomolar affinity in vitro.
  • HDX-MS and cryo-EM revealed distinct binding interfaces for HTT and HTT-HAP40.
  • Chemoproteomics confirmed selective binding in wildtype but not HTT-null cell lines.
  • HAP40 consistently copurified with HTT across various cell lines and HTT variants.

Conclusions:

  • Macrocyclic peptide binders represent promising selective chemical tools for studying the Huntingtin (HTT) protein.
  • These binders can engage distinct HTT and HTT-HAP40 interfaces.
  • The findings highlight the consistent presence of the HTT-HAP40 complex, relevant for understanding Huntington's disease.

Keywords:
HAP40HuntingtinHuntington diseasemacrocycles

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