There is strong epidemiological evidence that Parkinson’s Disease (PD) can originate in the gut prior to diagnosis of PD. Aggregates of misfolded alpha-synuclein protein (α-Syn) comprising the hallmark Lewy bodies of PD are hypothesized to propagate via the vagus nerve from the enteric nervous system (ENS) to the central nervous system (CNS) (Braak’s Hypothesis), further linking onset of PD to GI dysfunction. Enteric bacteria in the gut, including E. coli, secrete CsgA protein, which readily adopts a classic amyloid structure and aggregates to generate curli fibrils on the bacterial surface. Curli fibrils are a major component of biofilm, which mediates bacterial adhesion, community growth, and stress protection. Curli fibrils are structurally similar to misfolded α-Syn and have been shown to catalyze α-Syn aggregation in vitro. It has also been demonstrated that bacterial amyloid (CsgA) exposure induces motor and GI phenotypes, and α-synucleinopathy in an α-Syn overexpressing (ASO) mouse model of PD. The polyphenol epigallocatechin gallate (EGCG) blocks CsgA aggregation, resulting in improved motor symptoms and reduced α-synucleinopathy in the substantia nigra after oral dosing in mice. EGCG has several liabilities that limit its viability as a drug candidate, and initial attempts to overcome these liabilities through medicinal chemistry were only partially successful. Given these liabilities, Axial screened known α-Syn aggregation inhibitors chemically distinct from EGCG, utilizing in vitro CsgA aggregation and csgA gene expression assays to identify several chemically distinct leads. Further optimization led to novel, gut-selective small molecule inhibitors of CsgA aggregation, which, when dosed orally in the ASO mouse model, decreased csgA gene expression in the gut, improved motor symptoms, and reduced brain pathology. Taken together, these data suggest that targeting CsgA aggregation using gut-restricted small molecule inhibitors of CsgA aggregation is a promising approach to alter disease progression in PD patients.

Gut-selective small molecule inhibitors of aggregation of bacterial amyloid protein CsgA as potential disease-modifying agents for Parkinson’s disease

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