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J Biol Chem. 2016 Aug 26;291(35):18310-25. doi: 10.1074/jbc.M116.720243. Epub 2016 Jun 22.

Inhibition of Ral GTPases Using a Stapled Peptide Approach.

Author information

1
From the Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
2
Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas 75390-9039.
3
From the Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
4
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
5
From the Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom, do202@cam.ac.uk.
6
From the Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom, hrm28@cam.ac.uk.

Abstract

Aberrant Ras signaling drives numerous cancers, and drugs to inhibit this are urgently required. This compelling clinical need combined with recent innovations in drug discovery including the advent of biologic therapeutic agents, has propelled Ras back to the forefront of targeting efforts. Activated Ras has proved extremely difficult to target directly, and the focus has moved to the main downstream Ras-signaling pathways. In particular, the Ras-Raf and Ras-PI3K pathways have provided conspicuous enzyme therapeutic targets that were more accessible to conventional drug-discovery strategies. The Ras-RalGEF-Ral pathway is a more difficult challenge for traditional medicinal development, and there have, therefore, been few inhibitors reported that disrupt this axis. We have used our structure of a Ral-effector complex as a basis for the design and characterization of α-helical-stapled peptides that bind selectively to active, GTP-bound Ral proteins and that compete with downstream effector proteins. The peptides have been thoroughly characterized biophysically. Crucially, the lead peptide enters cells and is biologically active, inhibiting isoform-specific RalB-driven cellular processes. This, therefore, provides a starting point for therapeutic inhibition of the Ras-RalGEF-Ral pathway.

KEYWORDS:

Ral; Ras; autophagy; cell signaling; peptide chemical synthesis; peptides; protein-protein interaction; small GTPase; stapled peptides; therapeutics

PMID:
27334922
PMCID:
PMC5000079
DOI:
10.1074/jbc.M116.720243
[Indexed for MEDLINE]
Free PMC Article

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