Abstract
Specific protein–protein interactions (PPIs) constitute a key underlying mechanism for the presence of a multitude of intracellular signaling pathways, which are essential for the survival of normal and cancer cells. Specific molecular blockers for a crucial PPI would therefore be invaluable tools for an enhanced functional interrogation of the signaling pathway harboring this particular PPI. On the other hand, if a particular PPI is essential for the survival of cancer cells but is absent in or dispensable for the survival of normal cells, its specific molecular blockers could potentially be developed into effective anticancer therapeutics. Due to the flat and extended PPI interface, it would be conceivably difficult for small molecules to achieve an effective blockade, a problem which could be potentially circumvented with peptides or proteins. However, the well-documented proteolytic instability and cellular impermeability of peptides and proteins in general would make their developing into effective intracellular PPI blockers quite a challenge. With the advent of the peptide ‘stapling’ technology which was demonstrated to be able to stabilize the α-helical conformation of a peptide via bridging two neighboring amino-acid side chains with a ‘molecular staple’, a linear parent peptide could be transformed into a stronger PPI blocker with enhanced proteolytic stability and cellular permeability. This review will furnish an account on the peptide ‘stapling’ technology and its exploitation in efforts to achieve an enhanced functional interrogation or manipulation of intracellular signaling pathways especially those that are cancer relevant.
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Abbreviations
- Aib:
-
2-aminoisobutyric acid
- AKAP:
-
A-kinase anchoring protein
- AKB:
-
A-kinase binding
- BAD:
-
BCL-2-associated agonist of cell death
- Bad −/− :
-
BAD-null
- BAK:
-
BCL-2 antagonist/killer
- BAX:
-
BCL-2-associated X
- BCL-2:
-
B-cell lymphoma 2
- BCL9:
-
B-cell CLL/lymphoma 9
- BCL-W:
-
B-cell lymphoma gene-W
- BCL-XL:
-
B-cell lymphoma-extra large
- BFL-1/A1:
-
BCL-2-related protein A1
- BH3:
-
BCL-2 homology 3
- BID:
-
BH3 interacting domain death agonist
- BIM:
-
BCL-2 interacting mediator of cell death
- EED:
-
embryonic ectoderm development
- eIF4E:
-
eukaryotic initiation factor 4E
- EZH2:
-
enhancer of zeste homolog 2
- GK:
-
glucokinase
- GSIS:
-
glucose-stimulated insulin secretion
- hDM2:
-
human double minute 2
- hDM4:
-
human double minute 4
- hDMX:
-
human double minute X
- HIV-1:
-
human immunodeficiency virus-1
- IRS1:
-
insulin receptor substrate 1
- MAML1:
-
mastermind-like family co-activator protein 1
- MCL-1:
-
myeloid cell leukemia-1
- mDM2:
-
murine double minute 2
- mDM4:
-
murine double minute 4
- mDMX:
-
murine double minute X
- MOM:
-
mitochondrial outer membrane
- NR:
-
nuclear receptor
- PKA:
-
protein kinase A
- PKA-R:
-
protein kinase A—regulatory subunit
- PPI:
-
protein–protein interaction
- PRC2:
-
polycomb repressive complex 2
- RCM:
-
ring closing metathesis
- TCF4:
-
T-cell factor 4.
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Acknowledgements
WZ is a Jiangsu provincial specially appointed professor and a recipient of the Jiangsu provincial ‘innovation and venture talents’ award plan, and the associated financial supports to the completion of this manuscript are appreciated.
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He, Y., Chen, D. & Zheng, W. An enhanced functional interrogation/manipulation of intracellular signaling pathways with the peptide ‘stapling’ technology. Oncogene 34, 5685–5698 (2015). https://doi.org/10.1038/onc.2015.37
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DOI: https://doi.org/10.1038/onc.2015.37
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