Objective: The discovery of cell-permeable, orally bioavailable and brain penetrant small molecules with the potential of inhibiting aggregation and intracellular accumulation of pathological alpha-synuclein (a-syn) for therapeutic use.

Background: The accumulation of a-syn aggregates is a common pathological feature of Parkinson’s disease (PD) and synucleinopathies, linked to disease progression. Evidence from in vitro and animal models suggests that neuronal toxicity arises from the active process of a-syn aggregation. Therefore, agents that can interfere with this pathogenic process are expected to delay or stop disease progression.

Method: New compounds have been designed starting from AC Immune’s proprietary Morphomer® library and optimized for their activity and suitability as oral CNS drugs. The compounds were characterized in a series of biochemical and cellular functional assays to evaluate their capacity to inhibit a-syn aggregation. The adequacy of mouse pharmacokinetics, brain exposure and tolerability were evaluated after single and repeated dosing.

Results: Novel compounds which were able to significantly inhibit a-syn aggregation in vitro were identified, as demonstrated by 1) the reduction in β-sheet content monitored by Thioflavin T, 2) the prolongation of aggregation lag phase, and 3) the prevention of the transition of a-syn into insoluble conformations, shown by sedimentation analysis. Compound effects were confirmed in an orthogonal assay based on the fluorescence polarization principle measuring aggregate size and a-syn solubility. Selected compounds were further evaluated in rat neurons using diseased brain lysates to seed intracellular a-syn aggregation; compounds potently reduced the formation of aggregates, with nanomolar IC₅₀ values. Identified compounds show specific binding to aggregated a-syn (over monomer), with nanomolar dissociation constants. The compounds are orally bioavailable and brain penetrant and therefore suitable for in vivo proof-of-concept studies.

Conclusion: Through iterative medicinal chemistry optimization starting from our Morphomer® library, new compounds have been identified that inhibit in vitro the fibrillization of a-syn and thus have the potential to interfere with the downstream pathological processes leading to synucleinopathies. These aggregation inhibitors will be used in relevant animal models of PD and MSA to evaluate their potential as disease-modifying therapeutics.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/addressing-pathological-alpha-synuclein-aggregation-using-a-small-molecule-strategy/