Targeting the Genome-Stability Hub Ctf4 by Stapled-Peptide Design.
Lau, Yu Heng
Simon, Aline C
Angew Chem Int Ed Engl
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Wu, Y., Villa, F., Maman, J., Lau, Y. H., Dobnikar, L., Simon, A. C., Labib, K., et al. (2017). Targeting the Genome-Stability Hub Ctf4 by Stapled-Peptide Design.. Angew Chem Int Ed Engl, 56 (42)https://doi.org/10.1002/anie.201705611
The 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.
WELLCOME TRUST (104641/Z/14/Z)
European Research Council (279337)
External DOI: https://doi.org/10.1002/anie.201705611
This record's URL: https://www.repository.cam.ac.uk/handle/1810/275184