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Rational Design of High Affinity Peptides Validates Histone Chaperone ASF1 as a New Epigenetic Target in Cancer

ABSTRACT: Starting from the structure of the human ASF1-histone complex, we developed a rational design strategy combining epitope tethering and optimization of interface contacts to identify a potent peptide inhibitor with a dissociation constant of 3 nM. LC-MS/MS was used to identify in vivo targets of the most prominent peptide inhibitor.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Uterine Cervix

DISEASE(S): Cervical Adenocarcinoma

SUBMITTER: Valentin SABATET

LAB HEAD: Damarys Loew

PROVIDER: PXD013279 | Pride | 2019-09-25

REPOSITORIES: Pride

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Design on a Rational Basis of High-Affinity Peptides Inhibiting the Histone Chaperone ASF1.

Bakail May M Gaubert Albane A Andreani Jessica J Moal Gwenaëlle G Pinna Guillaume G Boyarchuk Ekaterina E Gaillard Marie-Cécile MC Courbeyrette Regis R Mann Carl C Thuret Jean-Yves JY Guichard Bérengère B Murciano Brice B Richet Nicolas N Poitou Adeline A Frederic Claire C Le Du Marie-Hélène MH Agez Morgane M Roelants Caroline C Gurard-Levin Zachary A ZA Almouzni Geneviève G Cherradi Nadia N Guerois Raphael R Ochsenbein Françoise F

Cell chemical biology 20190919 11

Anti-silencing function 1 (ASF1) is a conserved H3-H4 histone chaperone involved in histone dynamics during replication, transcription, and DNA repair. Overexpressed in proliferating tissues including many tumors, ASF1 has emerged as a promising therapeutic target. Here, we combine structural, computational, and biochemical approaches to design peptides that inhibit the ASF1-histone interaction. Starting from the structure of the human ASF1-histone complex, we developed a rational design strateg ...[more]

PMID: 31543461

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