Cell Membrane Composition Drives Selectivity and Toxicity of Designed Cyclic Helix-Loop-Helix Peptides with Cell Penetrating and Tumor Suppressor Properties

ACS Chemical Biology
Grégoire PhilippeSónia Troeira Henriques

Abstract

The tumor suppressor protein p53 is inactive in a large number of cancers, including some forms of sarcoma, breast cancer, and leukemia, due to overexpression of its intrinsic inhibitors MDM2 and MDMX. Reactivation of p53 tumor suppressor activity, via disruption of interactions between MDM2/X and p53 in the cytosol, is a promising strategy to treat cancer. Peptides able to bind MDM2 and/or MDMX were shown to prevent MDM2/X:p53 interactions, but most possess low cell penetrability, low stability, and/or high toxicity to healthy cells. Recently, the designed peptide cHLH-p53-R was reported to possess high affinity for MDM2, resistance toward proteases, cell-penetrating properties, and toxicity toward cancer cells. This peptide uses a stable cyclic helix-loop-helix (cHLH) scaffold, which includes two helices connected with a Gly loop and cyclized to improve stability. In the current study, we were interested in examining the cell selectivity of cHLH-p53-R, its cellular internalization, and ability to reactivate the p53 pathway. We designed analogues of cHLH-p53-R and employed biochemical and biophysical methodologies using in vitro model membranes and cell-based assays to compare their structure, activity, and mode-of-action. Our...Continue Reading

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Citations

May 18, 2020·The Journal of Biological Chemistry·Qingdan DuDavid J Craik
Feb 4, 2021·ACS Chemical Biology·Grégoire J-B PhilippeSónia T Henriques
Nov 28, 2020·Chembiochem : a European Journal of Chemical Biology·Jessica A I MullerDavid J Craik
Oct 5, 2021·Chembiochem : a European Journal of Chemical Biology·Daisuke FujiwaraIkuo Fujii

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