Preventing cell-to-cell tranmission of disordered proto-fibrils of $\alpha$-Synuclein

The cell-to-cell transmission of the oligomeric proto-fibrils of $\alpha$Synuclein ($\alpha$S) is believed to be a key driver in the progression of neurodegeneration including Parkinson's Disease. Here, we present a computational protocol for the design of inhibitors preventing the disordered C-terminal region of $\alpha$S from interacting with its neuronal cell surface receptor, LAG3. We begin with the structural characterization of the binding of the disordered $\alpha$S with LAG3 using information-driven docking from NMR derived constraints. Using this docked complex, we use partial diffusion and inverse folding to generate and design binders to LAG3. We perform exhaustive validation \textit{in silico} using molecular dynamics and the MM/PBSA-IE method. 12 binders were evaulated \textit{in vitro} of which several show pM-nM affinity binding (K$_\mathrm{D}$), as measured by BLI. The best performing binders effectively downregulate neurodegeneration in mammalian cells and the lead candidates will be further validated in animal models to show functional activity of preventing cell-to-cell transmission of $\alpha$S.