Novel Dimer Compounds That Bind α-Synuclein Can Rescue Cell Growth in a Yeast Model Overexpressing α-Synuclein. A Possible Prevention Strategy for Parkinson's Disease.

The misfolding of α-synuclein is a critical event in the death of dopaminergic neurons and the progression of Parkinson's disease. Previously, it was suggested that drugs, which bind to α-synuclein and form a loop structure between the N- and C-termini, tend to be neuroprotective, whereas others, which cause a more compact structure, tend to be neurotoxic. To improve the binding to α-synuclein, eight novel compounds were synthesized from a caffeine scaffold attached to (R,S)-1-aminoindan, (R,S)-nicotine, and metformin, and their binding to α-synuclein determined through nanopore analysis and isothermal titration calorimetry.

Drugs That Bind to α-Synuclein: Neuroprotective or Neurotoxic?

The misfolding of α-synuclein is a critical event in the death of dopaminergic neurons and the progression of Parkinson's disease. Drugs that bind to α-synuclein and form a loop structure between the N- and C-terminus tend to be neuroprotective, whereas others that cause a more compact structure tend to be neurotoxic. The binding of several natural products and other drugs that are involved in dopamine metabolism were investigated by nanopore analysis and isothermal titration calorimetry.

The use of nanopore analysis for discovering drugs which bind to α-synuclein for treatment of Parkinson's disease.

A major feature of Parkinson's disease is the formation of Lewy bodies in dopaminergic neurons which consist of misfolded α-synuclein. The binding of natural products to α-synuclein was evaluated by nanopore analysis and caffeine, curcumin, and nicotine all caused large conformational changes which may be related to their known neuroprotective effect in Parkinson's disease. The binding of the stereoisomers of nicotine were also studied by ITC, CD and NMR.