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

Proceedings of the National Academy of Sciences 2026 Open access

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Authors: Rebeka Fanti, Esther Wolf, Tatsuya Ikenoue, Justin C. Deme, Swati Balakrishnan, Brandon A. Keith, Matthew G. Alteen, Renu Chandrasekaran, Manisha Yadav, Ritika Bhajiawala, Suzanne Ackloo, Jia Feng
+6 more Mahmoud A. Pouladi, Aled M. Edwards, Derek J. Wilson, Susan M. Lea, Hiroaki Suga, Rachel J. Harding
DOI: 10.1073/pnas.2520462123
Cited by: 2
References: 55

Abstract

) 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.

Fields of Study & Subjects

Genetic Neurodegenerative Diseases Amyotrophic Lateral Sclerosis Research Neurological disorders and treatments

Publication details

Journal / source
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Volume
123
Issue
12
Pages
e2520462123–e2520462123
Publication date
16 March 2026
Language
EN