SK-129 is a blood-brain barrier-permeable inhibitor of α-synuclein ( αS ) oligomers with a K d of 221 nM. SK-129 preferentially binds to neurotoxic αS oligomers over physiological αS monomers, inhibits αS aggregation, blocks the interaction and co-aggregation of αS with tau protein, and prevents the maturation of αS-tau condensates into amyloid aggregates. SK-129 reduces ROS production, rescues dopaminergic neuron degeneration, improves motor function, restores endogenous dopamine synthesis, increases the number of Tyrosine Hydroxylase -positive neurons, prevents brain histopathological changes, alleviates neuroinflammation, and improves survival rates in relevant models. SK-129 can be used in research related to Parkinson's disease (PD) and Lewy body dementia (LBD) [1].
In Vivo, SK-129 (25-50 μM; administered on days 2 and 4, day 5) rescues DA neuron degeneration, motor deficits, oxidative stress, and behavioral deficits in both early and postdisease UA196 C. elegans PD models in a dose-dependent manner[1]. SK-129 (20 mg/kg; i.v.; every other day; 21 days) confers 100% survival up to 270 days, prevents PD-related weight loss, eliminates α-synuclein and α-synuclein-tau pathology, reduces neuroinflammation, and shows no systemic toxicity in the M83(A) mouse PD model[1].
In Vitro, SK-129 (SK-129F; 100 nM; until signal saturation) preferentially binds pathological αS oligomers and fibrils over physiological αS monomers, with a Kd value of 221 nM for αS oligomers[1]. SK-129 (10 μM; 12 h pre- or post-treatment) potently inhibits αS aggregation in αSA53T-YFP-expressing HEK293T cells mediated by NDE derived from Parkinson's disease (PD)[1]. SK-129 (1 μM) binds to αS-tau liquid condensates and inhibits their transition to toxic amyloid-like co-aggregates, instead inducing the formation of non-amyloid gel-like aggregates[1].
References:
[1]. Dohoney RA, et al. Foldamers rescue synucleinopathy phenotypes in multiple in vitro and in vivo models. Sci Transl Med. 2026;18(843):eadu1050.
In Vivo, SK-129 (25-50 μM; administered on days 2 and 4, day 5) rescues DA neuron degeneration, motor deficits, oxidative stress, and behavioral deficits in both early and postdisease UA196 C. elegans PD models in a dose-dependent manner[1]. SK-129 (20 mg/kg; i.v.; every other day; 21 days) confers 100% survival up to 270 days, prevents PD-related weight loss, eliminates α-synuclein and α-synuclein-tau pathology, reduces neuroinflammation, and shows no systemic toxicity in the M83(A) mouse PD model[1].
In Vitro, SK-129 (SK-129F; 100 nM; until signal saturation) preferentially binds pathological αS oligomers and fibrils over physiological αS monomers, with a Kd value of 221 nM for αS oligomers[1]. SK-129 (10 μM; 12 h pre- or post-treatment) potently inhibits αS aggregation in αSA53T-YFP-expressing HEK293T cells mediated by NDE derived from Parkinson's disease (PD)[1]. SK-129 (1 μM) binds to αS-tau liquid condensates and inhibits their transition to toxic amyloid-like co-aggregates, instead inducing the formation of non-amyloid gel-like aggregates[1].
References:
[1]. Dohoney RA, et al. Foldamers rescue synucleinopathy phenotypes in multiple in vitro and in vivo models. Sci Transl Med. 2026;18(843):eadu1050.