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

Akshay Chenna

Track: Biology: datasets and/or experimental results

Nature Biotechnology: No

Keywords: Intrinsically disordered proteins, diffusion, neurodegeneration, Parkinson's Disease

TL;DR: A computational protocol to target disordered protein interactions by designing pM affinity binders

Abstract: 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.

Anonymization: This submission has been anonymized for double-blind review via the removal of identifying information such as names, affiliations, and identifying URLs.

Presenter: ~Akshay_Chenna1

Format: Yes, the presenting author will attend in person if this work is accepted to the workshop.

Funding: No, the presenting author of this submission does *not* fall under ICLR’s funding aims, or has sufficient alternate funding.

Submission Number: 92