Protein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson’s phenotypes

Nicholas H. Stillman, Johnson A. Joseph, Jemil Ahmed, Charles Zuwu Baysah, Ryan A. Dohoney, Tyler D. Ball, Alexandra G. Thomas, Tessa C. Fitch, Courtney M. Donnelly and Sunil Kumar ()
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Nicholas H. Stillman: F.W. Olin Hall, 2190 E Iliff Ave, University of Denver
Johnson A. Joseph: F.W. Olin Hall, 2190 E Iliff Ave, University of Denver
Jemil Ahmed: 2155 E. Wesley Ave, Suite 579, University of Denver
Charles Zuwu Baysah: F.W. Olin Hall, 2190 E Iliff Ave, University of Denver
Ryan A. Dohoney: F.W. Olin Hall, 2190 E Iliff Ave, University of Denver
Tyler D. Ball: F.W. Olin Hall, 2190 E Iliff Ave, University of Denver
Alexandra G. Thomas: F.W. Olin Hall, 2190 E Iliff Ave, University of Denver
Tessa C. Fitch: 2155 E. Wesley Ave, Suite 579, University of Denver
Courtney M. Donnelly: F.W. Olin Hall, 2190 E Iliff Ave, University of Denver
Sunil Kumar: F.W. Olin Hall, 2190 E Iliff Ave, University of Denver

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: Abstract Abberent protein-protein interactions potentiate many diseases and one example is the toxic, self-assembly of α-Synuclein in the dopaminergic neurons of patients with Parkinson’s disease; therefore, a potential therapeutic strategy is the small molecule modulation of α-Synuclein aggregation. In this work, we develop an Oligopyridylamide based 2-dimensional Fragment-Assisted Structure-based Technique to identify antagonists of α-Synuclein aggregation. The technique utilizes a fragment-based screening of an extensive array of non-proteinogenic side chains in Oligopyridylamides, leading to the identification of NS132 as an antagonist of the multiple facets of α-Synuclein aggregation. We further identify a more cell permeable analog (NS163) without sacrificing activity. Oligopyridylamides rescue α-Synuclein aggregation mediated Parkinson’s disease phenotypes in dopaminergic neurons in early and post disease Caenorhabditis elegans models. We forsee tremendous potential in our technique to identify lead therapeutics for Parkinson’s disease and other diseases as it is expandable to other oligoamide scaffolds and a larger array of side chains.

Date: 2024
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DOI: 10.1038/s41467-024-47980-4

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