Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery

Scientific Reports
D TheanChristopher Brown

Abstract

Linear peptides can mimic and disrupt protein-protein interactions involved in critical cell signaling pathways. Such peptides however are usually protease sensitive and unable to engage with intracellular targets due to lack of membrane permeability. Peptide stapling has been proposed to circumvent these limitations but recent data has suggested that this method does not universally solve the problem of cell entry and can lead to molecules with off target cell lytic properties. To address these issues a library of stapled peptides was synthesized and screened to identify compounds that bound Mdm2 and activated cellular p53. A lead peptide was identified that activated intracellular p53 with negligible nonspecific cytotoxicity, however it still bound serum avidly and only showed a marginal improvement in cellular potency. These hurdles were overcome by successfully identifying a pyridinium-based cationic lipid formulation, which significantly improved the activity of the stapled peptide in a p53 reporter cell line, principally through increased vesicular escape. These studies underscore that stapled peptides, which are cell permeable and target specific, can be identified with rigorous experimental design and that these propert...Continue Reading

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Citations

Apr 28, 2018·Chembiochem : a European Journal of Chemical Biology·Baggio A EvangelistaDmitry M Kolpashchikov
Jul 11, 2019·Chemical Communications : Chem Comm·Emil S IqbalMatthew C T Hartman
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Dec 12, 2019·The Journal of Organic Chemistry·Tsz Ying YuenCharles W Johannes
Sep 16, 2021·Molecular Pharmaceutics·Zhengyuan ZhouSatish K Chitneni

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Methods Mentioned

BETA
chemical
phage display
BRET
FCS
confocal microscopy
Fluorescence
Assay

Software Mentioned

SaintPhD

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