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dc.contributor.authorWu, Yutengen
dc.contributor.authorVilla, Fabrizioen
dc.contributor.authorMaman, Josephen
dc.contributor.authorLau, Yu Hengen
dc.contributor.authorDobnikar, Linaen
dc.contributor.authorSimon, Aline Cen
dc.contributor.authorLabib, Karimen
dc.contributor.authorSpring, Daviden
dc.contributor.authorPellegrini, Lucaen
dc.date.accessioned2018-04-26T10:28:01Z
dc.date.available2018-04-26T10:28:01Z
dc.date.issued2017-10-09en
dc.identifier.issn1433-7851
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/275184
dc.description.abstractThe exploitation of synthetic lethality by small-molecule targeting of pathways that maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND-1 protein hub, which links DNA replication, repair, and chromosome segregation, represents a novel target for the synthetic lethality approach. Herein, we report the design, optimization, and validation of double-click stapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. By screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, submicromolar binding to Ctf4. The mode of interaction with Ctf4 was confirmed by a crystal structure of the stapled Sld5 peptide bound to Ctf4. The stapled Sld5 peptide was able to displace the Ctf4 partner DNA polymerase α from the replisome in yeast extracts. Our study provides proof-of-principle evidence for the development of small-molecule inhibitors of the human CTF4 orthologue AND-1.
dc.languageengen
dc.titleTargeting the Genome-Stability Hub Ctf4 by Stapled-Peptide Design.en
dc.typeArticle
prism.issueIdentifier42en
prism.publicationDate2017en
prism.publicationNameAngew Chem Int Ed Englen
prism.volume56en
dc.identifier.doi10.17863/CAM.22366
dcterms.dateAccepted2017-08-17en
rioxxterms.versionofrecord10.1002/anie.201705611en
rioxxterms.versionAM*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-10-09en
dc.contributor.orcidSpring, David [0000-0001-7355-2824]
dc.contributor.orcidPellegrini, Luca [0000-0002-9300-497X]
dc.identifier.eissn1521-3773
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWELLCOME TRUST (104641/Z/14/Z)
pubs.funder-project-idEuropean Research Council (279337)
pubs.funder-project-idEPSRC (EP/K039520/1)
cam.issuedOnline2017-08-17en
rioxxterms.freetoread.startdate2018-08-17


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