Skip to main content

De Novo Peptide Design and Experimental Validation of Histone Methyltransferase Inhibitors

Author(s): Smadbeck, James; Peterson, Meghan B; Zee, Barry M; Garapaty, Shivani; Mago, Aashna; et al

Download
To refer to this page use: http://arks.princeton.edu/ark:/88435/pr1dc4p
Full metadata record
DC FieldValueLanguage
dc.contributor.authorSmadbeck, James-
dc.contributor.authorPeterson, Meghan B-
dc.contributor.authorZee, Barry M-
dc.contributor.authorGarapaty, Shivani-
dc.contributor.authorMago, Aashna-
dc.contributor.authorLee, Christina-
dc.contributor.authorGiannis, Athanassios-
dc.contributor.authorTrojer, Patrick-
dc.contributor.authorGarcia, Benjamin A-
dc.contributor.authorFloudas, Christodoulos A-
dc.date.accessioned2021-10-08T19:58:46Z-
dc.date.available2021-10-08T19:58:46Z-
dc.date.issued2014-02-28en_US
dc.identifier.citationSmadbeck, James, Meghan B. Peterson, Barry M. Zee, Shivani Garapaty, Aashna Mago, Christina Lee, Athanassios Giannis, Patrick Trojer, Benjamin A. Garcia, and Christodoulos A. Floudas. "De Novo Peptide Design and Experimental Validation of Histone Methyltransferase Inhibitors." PloS ONE 9, no. 2 (2014). doi: 10.1371/journal.pone.0090095en_US
dc.identifier.urihttp://arks.princeton.edu/ark:/88435/pr1dc4p-
dc.description.abstractHistones are small proteins critical to the efficient packaging of DNA in the nucleus. DNA–protein complexes, known as nucleosomes, are formed when the DNA winds itself around the surface of the histones. The methylation of histone residues by enhancer of zeste homolog 2 (EZH2) maintains gene repression over successive cell generations. Overexpression of EZH2 can silence important tumor suppressor genes leading to increased invasiveness of many types of cancers. This makes the inhibition of EZH2 an important target in the development of cancer therapeutics. We employed a three-stage computational de novo peptide design method to design inhibitory peptides of EZH2. The method consists of a sequence selection stage and two validation stages for fold specificity and approximate binding affinity. The sequence selection stage consists of an integer linear optimization model that was solved to produce a rank-ordered list of amino acid sequences with increased stability in the bound peptide-EZH2 structure. These sequences were validated through the calculation of the fold specificity and approximate binding affinity of the designed peptides. Here we report the discovery of novel EZH2 inhibitory peptides using the de novo peptide design method. The computationally discovered peptides were experimentally validated in vitro using dose titrations and mechanism of action enzymatic assays. The peptide with the highest in vitro response, SQ037, was validated in nucleo using quantitative mass spectrometry-based proteomics. This peptide had an IC50 of 13.5 M, demonstrated greater potency as an inhibitor when compared to the native and K27A mutant control peptides, and demonstrated competitive inhibition versus the peptide substrate. Additionally, this peptide demonstrated high specificity to the EZH2 target in comparison to other histone methyltransferases. The validated peptides are the first computationally designed peptides that directly inhibit EZH2. These inhibitors should prove useful for further chromatin biology investigations.en_US
dc.format.extente90095en_US
dc.language.isoen_USen_US
dc.relation.ispartofPLoS ONEen_US
dc.rightsFinal published version. This is an open access article.en_US
dc.titleDe Novo Peptide Design and Experimental Validation of Histone Methyltransferase Inhibitorsen_US
dc.typeJournal Articleen_US
dc.identifier.doidoi:10.1371/journal.pone.0090095-
dc.identifier.eissn1932-6203-
pu.type.symplectichttp://www.symplectic.co.uk/publications/atom-terms/1.0/journal-articleen_US

Files in This Item:
File Description SizeFormat 
HistoneMethyltransferaseInhibitors.PDF2.11 MBAdobe PDFView/Download


Items in OAR@Princeton are protected by copyright, with all rights reserved, unless otherwise indicated.