2. Academic Validation
  3. Foldamers rescue synucleinopathy phenotypes in multiple in vitro and in vivo models

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

  • Sci Transl Med. 2026 Apr;18(843):eadu1050. doi: 10.1126/scitranslmed.adu1050.
Ryan A Dohoney 1 2,  L Palanikumar 3,  Emily Oldani 1 2 4,  Charles Zuwu Baysah 1 2,  Johnson A Joseph 1 2,  David Polanco 5,  Paula Santos-Otte 6,  Nicholas H Stillman 1 2,  Peter Corcoran 1 2 4,  Tyler D Ball 1 2,  Tessa C Fitch 2,  Jemil Ahmed 2 3,  Ifunayachi Ogbonna-Ukuku 1 2,  Kevin M Reynolds Caicedo 2 7,  Ying Liu 8,  Maureen A Leehey 8,  Daniel A Linseman 2 4 7,  Daniel A Paredes 2 9,  Melissa Birol 6,  Nunilo Cremades 5,  Mazin Magzoub 3,  Sunil Kumar 1 2 4
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, F. W. Olin Hall, 2190 E. Iliff Ave., University of Denver, Denver, CO 80210, USA.
  • 2 Knoebel Institute for Healthy Aging, 2155 E. Wesley Ave., Suite 579, University of Denver, Denver, CO 80208, USA.
  • 3 Biology Program, Division of Science, New York University Abu Dhabi, PO Box 129188, Saadiyat Island, Abu Dhabi, United Arab Emirates.
  • 4 Molecular and Cellular Biophysics Program, Boettcher West, Room 228, 2050 E. Iliff Ave., University of Denver, Denver, CO 80210, USA.
  • 5 Institute for Biocomputation and Physics of Complex Systems (BIFI) and Department of Biochemistry and Molecular and Cellular Biology, University of Zaragoza, Zaragoza 50009, Spain.
  • 6 Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Berlin 10115, Germany.
  • 7 Department of Biological Sciences, F. W. Olin Hall, 2190 E. Iliff Ave., University of Denver, Denver, CO 80210, USA.
  • 8 Department of Neurology, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO 80045, USA.
  • 9 Ritchie School of Engineering and Computer Science, 2155 E. Wesley Ave., University of Denver, Denver, CO 80210, USA.
PMID: 41920967 DOI: 10.1126/scitranslmed.adu1050
Abstract

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.

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