1 research outputs found
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 (<i>R</i>,<i>S</i>)-1-aminoindan, (<i>R</i>,<i>S</i>)-nicotine, and metformin, and their
binding to α-synuclein determined through nanopore analysis
and isothermal titration calorimetry. The ability of the dimers to
interact with α-synuclein in a cell system was assayed in a
yeast model of PD which expresses an AS-GFP (α-synuclein-Green
Fluorescent Protein) construct under the control of a galactose promoter.
In 5 mM galactose this yeast strain will not grow and large cytoplasmic
foci are observed by fluorescent microscopy. Two of the dimers, C<sub>8</sub>-6-I and C<sub>8</sub>-6-N, at a concentration of 0.1 ÎĽM
allowed the yeast to grow normally in 5 mM galactose and the AS-GFP
became localized to the periphery of the cell. Both dimers were superior
when compared to the monomeric compounds. The presence of the dimers
also caused the disappearance of preformed cytoplasmic foci. Nanopore
analysis of C<sub>8</sub>-6-I and C<sub>8</sub>-6-N were consistent
with simultaneous binding to both the N- and C-terminus of α-synuclein
but the binding constants were only 10<sup>5</sup> M<sup>–1</sup>