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

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a Cytosine-Adenosine-Guanine (CAG) repeat expansion in the <i>Huntingtin</i> (<i>HTT</i>) gene, with no disease-modifying therapies currently available. The precise molecular function of the HTT protein is unclear, and the lack of selective chemical tools has limited functional studies. We have identified and characterized macrocyclic peptide binders targeting HTT. These binders exhibit low-nanomolar affinity in vitro and engage distinct HTT and HTT-HAP40 interfaces, as revealed by hydrogen-deuterium exchange mass spectrometry and cryoelectron microscopy. Chemoproteomics confirmed selective binding in cell extracts from wildtype but not HTT-null cell lines. HAP40 consistently and stoichiometrically copurified with HTT across cell lines, including with HTT variants containing different CAG repeat lengths, highlighting the broad presence of the HTT-HAP40 complex.

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Journal
Proceedings of the National Academy of Sciences
Published
2026-03-16
DOI
https://doi.org/10.1073/pnas.2520462123
Primary Topic
Genetic Neurodegenerative Diseases
Type
article
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article

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

Hiroaki Suga, Tatsuya Ikenoue, Derek J. Wilson, Renu Chandrasekaran et al.
Proceedings of the National Academy of Sciences
Genetic Neurodegenerative Diseases
article

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

Hiroaki Suga, Tatsuya Ikenoue, Derek J. Wilson, Renu Chandrasekaran, Esther Wolf, Matthew G. Alteen, Jia Feng, Susan M. Lea, Justin C. Deme, Suzanne Ackloo, Ritika Bhajiawala, Swati Balakrishnan, Aled M. Edwards, Brandon A. Keith, Rebeka Fanti, Mahmoud A. Pouladi, Rachel J. Harding, Manisha Yadav
article en

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a Cytosine-Adenosine-Guanine (CAG) repeat expansion in the <i>Huntingtin</i> (<i>HTT</i>) gene, with no disease-modifying therapies currently available. The precise molecular function of the HTT protein is unclear, and the lack of selective chemical tools has limited functional studies. We have identified and characterized macrocyclic peptide binders targeting HTT. These binders exhibit low-nanomolar affinity in vitro and engage distinct HTT and HTT-HAP40 interfaces, as revealed by hydrogen-deuterium exchange mass spectrometry and cryoelectron microscopy. Chemoproteomics confirmed selective binding in cell extracts from wildtype but not HTT-null cell lines. HAP40 consistently and stoichiometrically copurified with HTT across cell lines, including with HTT variants containing different CAG repeat lengths, highlighting the broad presence of the HTT-HAP40 complex.

Proceedings of the National Academy of SciencesVol. 123(12)
3M (United States) (US), University of British Columbia (CA), University of Toronto (CA), York University (CA), Cancer Institute (WIA) (IN), Princess Margaret Cancer Centre (CA), Structural Genomics Consortium (CA), Center for Cancer Research (US), Institute of Aging (CA), The University of Tokyo (JP)
Openalex Percentile: Top 20%
Genetic Neurodegenerative Diseases
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