Anle138b, an Oligomeric Aggregation Inhibitor, Blocks the Formation of PrPSc and of α-Synuclein (α-syn)

The cellular prion protein, PrPSc, is a small, cell surface glycoprotein with a function that is currently somewhat ill defined. The highest level of expression of PrPC is in the central nervous system (CNS). However, both transcript and protein can be detected at lower levels in a variety of other tissue/cell types. The PrPSc is the primary player in a devastating class of neurodegenerative disorders (transmissible spongiform encephalopathies or prion diseases). During pathogenesis of a prion disease the normal form of the PrPSc  misfolds into an insoluble form that aggregates into large assemblies, including amyloid fibrils and plaques. The misfolded protein (PrPTSE, the TSE isoform) accumulates during disease in the brain of affected individuals, leading inextricably to death.

α-Synuclein (α-syn) is a presynaptic neuronal protein that is linked genetically and neuropathologically to Parkinson’s disease (PD). And the neuropathological hallmark of PD is the accumulation of alpha-synuclein (α-syn). Importantly, α-syn may contribute to PD pathogenesis in a number of ways. Generally, its aberrant soluble oligomeric conformations are the toxic species that mediate disruption of cellular homeostasis and neuronal death, through effects on various intracellular targets. Furthermore, secreted α-syn may exert deleterious effects on neighboring cells, including seeding of aggregation, thus possibly contributing to disease propagation.

Anle138b: a novel oligomer modulator.

Anle138b, an oligomeric aggregation inhibitor, blocks the formation of pathological aggregates of PrPSc and of α-syn. The pathological aggregates exist in PD and other synucleinopathies. Notably, anle138b strongly inhibited prion strains including BSE-derived and human prions. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b has low toxicity and an excellent oral bioavailability and blood-brain-barrier penetration.

In summary, Anle138b, an oligomeric aggregation inhibitor inhibits formation of pathological PrPSc and α-syn aggregates. Anle138b has the potential for neurodegenerative diseases research such as prion and Parkinson’s disease.

References:

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[2]. Fields CR, et, al. Front Mol Neurosci. 2019 Dec 5;12:299.