Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions
Michael F. Jobling,
Shyra J. Gardai,
Carlos W. Bertoncini,
Mariano C. Tabios,
Mitali A. Tambe,
John P. Anderson,
David A. Agard,
Posted 24 May 2019
bioRxiv DOI: 10.1101/646505 (published DOI: 10.1038/s41598-019-52598-4)
Posted 24 May 2019
The over-expression and aggregation of alpha-synuclein (aSyn) are linked to the onset and pathology of Parkinson's disease. Native monomeric aSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of aSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric aSyn is incubated with microchips arrayed with tethered compounds, we identified novel aSyn interacting drug-like compounds. Because these small molecules could impact a variety of aSyn forms present in the ensemble, we tested representative hits for impact on multiple aSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits aSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by aSyn overexpression, and a compound blocking cellular transmission of aSyn. Our studies demonstrate that drug-like small molecules that interact with native aSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of aSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson's disease.
- Downloaded 333 times
- Download rankings, all-time:
- Site-wide: 65,741 out of 118,598
- In neuroscience: 10,228 out of 18,632
- Year to date:
- Site-wide: 95,314 out of 118,598
- Since beginning of last month:
- Site-wide: 107,596 out of 118,598
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!