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Protease-resistant and cell-permeable double-stapled peptides targeting the Rab8a GTPase
- Source :
- Cromm, P M, Spiegel, J, Kuchler, P, Dietrich, L, Kriegesmann, J, Wendt, M, Goody, R S, Waldmann, H & Grossmann, T N 2016, ' Protease-resistant and cell-permeable double-stapled peptides targeting the Rab8a GTPase. ', ACS chemical biology, vol. 11, pp. 2375-2382 . https://doi.org/10.1021/acschembio.6b00386, ACS chemical biology, 11, 2375-2382. American Chemical Society
- Publication Year :
- 2016
- Publisher :
- American Chemical Society, 2016.
-
Abstract
- Small GTPases comprise a family of highly relevant targets in chemical biology and medicinal chemistry research and have been considered "undruggable" due to the persisting lack of effective synthetic modulators and suitable binding pockets. As molecular switches, small GTPases control a multitude of pivotal cellular functions, and their dysregulation is associated with many human diseases such as various forms of cancer. Rab-GTPases represent the largest subfamily of small GTPases and are master regulators of vesicular transport interacting with various proteins via flat and extensive protein-protein interactions (PPIs). The only reported synthetic inhibitor of a PPI involving an activated Rab GTPase is the hydrocarbon stapled peptide StRIP3. However, this macrocyclic peptide shows low proteolytic stability and cell permeability. Here, we report the design of a bioavailable StRIP3 analogue that harbors two hydrophobic cross-links and exhibits increased binding affinity, combined with robust cellular uptake and extremely high proteolytic stability. Localization experiments reveal that this double-stapled peptide and its target protein Rab8a accumulate in the same cellular compartments. The reported approach offers a strategy for the implementation of biostability into conformationally constrained peptides while supporting cellular uptake and target affinity, thereby conveying drug-like properties.
- Subjects :
- 0301 basic medicine
Subfamily
Cell
Chemical biology
Biological Availability
GTPase
Biology
Biochemistry
Permeability
03 medical and health sciences
GTP-binding protein regulators
SDG 3 - Good Health and Well-being
medicine
Humans
Amino Acid Sequence
Peptide sequence
General Medicine
Cell biology
Vesicular transport protein
030104 developmental biology
medicine.anatomical_structure
rab GTP-Binding Proteins
Molecular Medicine
Rab
Peptides
HeLa Cells
Peptide Hydrolases
Subjects
Details
- Language :
- English
- ISSN :
- 15548937 and 15548929
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- ACS chemical biology
- Accession number :
- edsair.doi.dedup.....a1e6c02b5497013c133921e7b5b74ba8
- Full Text :
- https://doi.org/10.1021/acschembio.6b00386