High-affinity, structure-validated and selective macrocyclic peptide tools for chemical biology studies of Huntingtin - PubMed
4 hours ago
- #Huntington's disease
- #HTT-HAP40 complex
- #Macrocyclic peptides
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin (HTT) gene.
- No disease-modifying therapies are currently available for HD.
- Macrocyclic peptide binders targeting HTT have been identified and characterized, showing low-nanomolar affinity in vitro.
- These binders 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.