Foldamers rescue synucleinopathy phenotypes in multiple in vitro and in vivo models

Dohoney, Ryan A. ; Palanikumar, L. ; Oldani, Emily ; Baysah, Charles Zuwu ; Joseph, Johnson A. ; Polanco, David (Universidad de Zaragoza) ; Santos-Otte, Paula ; Stillman, Nicholas H. ; Corcoran, Peter ; Ball, Tyler D. ; Fitch, Tessa C. ; Ahmed, Jemil ; Ogbonna-Ukuku, Ifunayachi ; Reynolds Caicedo, Kevin M. ; Liu, Ying ; Leehey, Maureen A. ; Linseman, Daniel A. ; Paredes, Daniel A. ; Birol, Melissa ; Cremades, Nunilo (Universidad de Zaragoza) ; Magzoub, Mazin ; Kumar, Sunil

Resumen: Synucleinopathies is an umbrella term for multiple neurological disorders, including Parkinson’s disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA). A central pathological hallmark of synucleinopathies is the aggregation of α-synuclein (αS, a neuronal protein) and its prion-like spread. Therefore, inhibition of αS aggregation and spread is considered a viable therapeutic approach for the treatment of synucleinopathies. Foldamers are synthetic ligands that mimic the secondary structure of proteins. Using an oligoquinoline (OQ) scaffold–based foldamer approach, we have previously identified a foldamer (SK-129) that potently inhibits αS aggregation. Here, using a wide range of biophysical, cellular, and in vivo methods, we showed that SK-129 rescued synucleinopathy phenotypes in cellular, Caenorhabditis elegans, and human induced pluripotent stem cell (iPSC)– derived neuron models. SK-129 specifically bound to neurotoxic αS oligomers with ~6-fold higher affinity (Kd = 221 ± 29 nM) than to physiological αS monomer, validating αS oligomers as a therapeutic target. Furthermore, SK-129 efficiently crossed the blood-brain barrier (BBB) and exhibited favorable pharmaceutical properties in mice. Treatment with SK-129 prevented brain histopathology and increased survival in a mouse model expressing human A53T mutant αS without showing any apparent cytotoxicity. SK-129 inhibited αS aggregation mediated by exosomes derived from C. elegans or patients with PD in HEK293T reporter cells. SK-129 completely inhibited the coaggregation of αS-tau, a pathological biomarker for LBD in both cellular and mouse models. Overall, we report a potent foldamer with therapeutic potential for PD and LBD.

Idioma: Inglés

DOI: 10.1126/scitranslmed.adu1050

Año: 2026

Publicado en: SCIENCE TRANSLATIONAL MEDICINE 18, 843 (2026), [17 pp.]
ISSN: 1946-6234

Financiación: info:eu-repo/grantAgreement/ES/AEI/PID2022-136997NB-I00

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)