170409 20260420103355.0 doi 10.1126/scitranslmed.adu1050 sideral 148875 ART-2026-148875 eng Dohoney, Ryan A. Foldamers rescue synucleinopathy phenotypes in multiple in vitro and in vivo models 2026 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. Access copy available to the general public Unrestricted info:eu-repo/grantAgreement/ES/AEI/PID2022-136997NB-I00 info:eu-repo/semantics/openAccess by-nd https://creativecommons.org/licenses/by-nd/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Palanikumar, L. Oldani, Emily Baysah, Charles Zuwu Joseph, Johnson A. Polanco, David Universidad de Zaragoza (orcid)0000-0002-0005-6712 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 (orcid)0000-0002-9138-6687 Magzoub, Mazin Kumar, Sunil 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 18, 843 (2026), [17 pp.] Sci.Transl.Med. SCIENCE TRANSLATIONAL MEDICINE 1946-6234 2076020 http://zaguan.unizar.es/record/170409/files/texto_completo.pdf Versión publicada 3491022 http://zaguan.unizar.es/record/170409/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:170409 articulos driver 2026-04-18-10:49:02 ARTICLE