Targeting the Genome-Stability Hub Ctf4 by Stapled-Peptide Design

Yuteng Wu, Fabrizio Villa, Joseph Maman, Yu Heng Lau, Lina Dobnikar, Aline C. Simon, Karim Labib, David R. Spring (Lead / Corresponding author), Luca Pellegrini (Lead / Corresponding author)

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13 Citations (Scopus)
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Abstract

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 polymeraseα 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.

Original languageEnglish
Pages (from-to)12866-12872
Number of pages8
JournalAngewandte Chemie International Edition
Volume56
Early online date7 Sep 2017
DOIs
Publication statusPublished - 9 Oct 2017

Keywords

  • Chemical biology
  • Chromosome stability
  • Ctf4 protein
  • Protein-protein interactions
  • Stapled peptides

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    Wu, Y., Villa, F., Maman, J., Lau, Y. H., Dobnikar, L., Simon, A. C., Labib, K., Spring, D. R., & Pellegrini, L. (2017). Targeting the Genome-Stability Hub Ctf4 by Stapled-Peptide Design. Angewandte Chemie International Edition, 56, 12866-12872. https://doi.org/10.1002/anie.201705611