The discovery and maturation of peptide biologics targeting the small G protein Cdc42: a bioblockade for Ras-driven signalling

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Tetley, George JN 
Murphy, Natasha P 
Bonetto, Stephane 
Ivanova-Berndt, Gabriela 
Revell, Jefferson 

jats:pAberrant Ras signalling drives 30% of cancers and inhibition of Rho family small-GTPase signalling has been shown to combat Ras-driven cancers. Here we present the discovery of a 16mer cyclic peptide that binds to Cdc42 with nanomolar affinity. Affinity maturation of this sequence has produced a panel of derived candidates with increased affinity and modulated specificity for other closely related small-GTPases. The structure of the tightest binding peptide was solved by NMR and its binding site on Cdc42 determined. Addition of a cell penetrating sequence allowed the peptides to access the cell interior and engage with their target(s), modulating signalling pathways. In Ras-driven cancer cell models, the peptides have an inhibitory effect on proliferation and show suppression of both invasion and motility. As such they represent promising candidates for Rho-family small GTPase inhibitors and therapeutics targeting Ras-driven cancers. Our data adds to the growing literature demonstrating that peptides are establishing their place in the biologics arm of drug discovery.</jats:p>

CDC42, GTPase Kras (KRAS), biologics, cancer, cancer therapeutics, cell migration, cell proliferation, cell signaling, cyclic peptide, drug discovery, nuclear magnetic resonance (NMR), peptide conformation, Binding Sites, Cell Movement, Cell Proliferation, Cell-Penetrating Peptides, Drug Discovery, GTP Phosphohydrolases, Humans, Molecular Structure, Neoplasm Invasiveness, Neoplasms, Peptides, Cyclic, Signal Transduction, cdc42 GTP-Binding Protein, ras Proteins
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Journal of Biological Chemistry
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American Society for Biochemistry & Molecular Biology (ASBMB)
MRC (MR/K017101/1)
Biotechnology and Biological Sciences Research Council (BB/M011194/1)
This research was supported by an MRC CASE Studentship (MR/K017101/1) to DO and RNC, a BBSRC DTP iCASE Studentship (BB/M011194/1) to DO and JR and a short-term Glover Research Fund Fellowship to GJNT.