Inhibit the formation of toxic aggregates of misfolded proteins
Oligomeric aggregates of disease-related misfolded proteins disrupt cell function and provoke inflammatory responses that are implicated in the pathogenesis and progression of neurodegenerative disorders. By contrast, the large end-stage fibrils may be relatively less toxic. This suggests that intervening in the earliest steps of protein aggregation, rather than targeting pre-existing fibrils, may provide the best opportunity for therapeutic benefit. The first pathological protein to be targeted by Neuropore Therapies using this approach was alpha-synuclein which is the primary constituent of intracellular inclusion bodies found in Parkinson’s disease and related synucleinopathies. Neuropore’s clinical stage compound, NPT200-11, acts by targeting an early “propagating” step in the formation of alpha-synuclein toxic protein aggregates. NPT200-11 was the product of a discovery program that used molecular dynamic modeling and direct biophysical measures to identify compounds that specifically disrupt alpha-synuclein dimerization and hence, the formation of toxic oligomeric aggregates implicated in the genesis and progression of Parkinson’s disease.