Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 18, Pages 13693-13703Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01043
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Funding
- High-Performance Computing Platform of Peking University
- National Key Research and Development Program Synthetic Biology Key Special Project of China [2018YFA0902504]
- National Natural Science Foundation of China [21778009, 21977010]
- Natural Science Foundation of Guangdong Province [2019A1515110487, 2020A1515010522, 2019A1515111184]
- Shenzhen Science and Technology Innovation Committee [JCYJ20180507181527112, JCYJ20180508152213145, JCYJ20170817172023838]
- China Postdoctoral Science Foundation [2021M690220]
- Beijing National Laboratory of Molecular Science [BNLMS20160112]
- Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions [2019SHIBS0004]
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Disrupting the interaction between HIF1 alpha and p300 by a constrained peptide inhibitor is a promising strategy for modulating the hypoxia response of tumor cells. The study demonstrates that stabilized peptides derived from CITED2 using helix-stabilizing methods show potential as candidates for modulating hypoxia-inducible signaling.
Disrupting the interaction between HIF1 alpha and p300 is a promising strategy to modulate the hypoxia response of tumor cells. Herein, we designed a constrained peptide inhibitor derived from the CITED2/p300 complex to disturb the HIF1 alpha/p300 interaction. Through truncation/mutation screening and a terminal aspartic acid-stabilized strategy, a constrained peptide was constructed with outstanding biochemical/biophysical properties, especially in binding affinity, cell penetration, and serum stability. To date, our study was the first one to showcase that stabilized peptides derived from CITED2 using helix-stabilizing methods acted as a promising candidate for modulating hypoxia-inducible signaling.
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