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20190625_NMilosevich_peptidic_inhibitors_polycomb_paralog_manuscript_and_SI.pdf (6.02 MB)
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Pan-Specific and Partially Selective Dye-Labeled Peptidic Inhibitors of the Polycomb Paralog Proteins

preprint
submitted on 12.07.2019 and posted on 15.07.2019 by Natalia Milosevich, James McFarlane, Michael Gignac, Janessa Li, Tyler Brown, Chelsea Wilson, Lindsay Devorkin, Caitlin Croft, Rebecca Hof, Irina Paci, Julian Lum, Fraser Hof

Epigenetic regulation of gene expression is in part controlled by post-translational modifications on histone proteins. Histone methylation is a key epigenetic mark that controls gene transcription and repression. There are five human polycomb paralog proteins (Cbx2/4/6/7/8) which use their chromodomains to recognize trimethylated lysine 27 on Histone 3 (H3K27me3). Recognition of the methyllysine side chain is achieved through multiple cation-pi interactions within an ‘aromatic cage’ motif. Despite high structural similarity within the chromodomains of this protein family, they each have unique functional roles and are linked to different cancers. Selective inhibition of different CBX proteins is highly desirable for both fundamental studies and potential therapeutic applications. We will report on a series of peptidic inhibitors that selectively target certain polycomb paralogs. We have identified peptidic scaffolds with sub-micromolar potency, and will report examples that are pan-specific and that are partially selective for individual members within the family. The data presented include extensive new synthesis with characterization by LC, Mass Spectrometry, and NMR. The binding interactions are measured by fluorescence polarization, molecular dynamics simulations, and protein microarray assays. These results highlight important structure-activity relationships that allow for selectivity to be achieved through interactions outside of the methyllysine binding aromatic cage motif.

Funding

Prostate Cancer Foundation of BC

WestCoast Motorcycle Ride to Live

Canadian Cancer Society Innovation Grant 703789

History

Email Address of Submitting Author

fhof@uvic.ca

Institution

University of Victoria

Country

Canada

ORCID For Submitting Author

0000-0003-4658-9132

Declaration of Conflict of Interest

The authors declare no conflict of interest

Version Notes

Submitted V1

Exports