Delivery to, and Reactivation of, the p53 Pathway in Cancer Cells Using a Grafted Cyclotide Conjugated with a Cell-Penetrating Peptide.

Peptides are promising drug modalities that can modulate protein-protein interactions, but their application is hampered by their limited ability to reach intracellular targets. Here, we improved the cytosolic delivery of a peptide blocking p53:MDM2/X interactions using a cyclotide as a stabilizing scaffold. We applied several design strategies to improve intracellular delivery and found that the conjugation of the lead cyclotide to the cyclic cell-penetrating peptide cR10 was the most effective.

Cyclic peptide scaffold with ability to stabilize and deliver a helical cell-impermeable cargo across membranes of cultured cancer cells.

Cell penetrating peptides (CPPs) are valuable tools for developing anticancer therapies due to their ability to access intracellular targets, including protein-protein interactions. cPF4PD is a newly described CPP designed from a transduction domain of the human defense protein platelet factor 4 (PF4), that also has antimalarial activity. The cPF4PD peptide recapitulates the helical structure of the PF4 domain and maintains activity against intracellular malaria parasites a selective membrane-active mechanism.

Angler Peptides: Macrocyclic Conjugates Inhibit p53:MDM2/X Interactions and Activate Apoptosis in Cancer Cells.

Peptides are being developed as targeted anticancer drugs to modulate cytosolic protein-protein interactions involved in cancer progression. However, their use as therapeutics is often limited by their low cell membrane permeation and/or inability to reach cytosolic targets. Conjugation to cell penetrating peptides has been successfully used to improve the cytosolic delivery of high affinity binder peptides, but cellular uptake does not always result in modulation of the targeted pathway.

Converting peptides into drugs targeting intracellular protein-protein interactions.

Peptides are gaining increasing attention as therapeutics to target intracellular protein-protein interactions that are involved in disease progression. In this review, we discuss how peptides that are able to bind and inhibit a therapeutic target can be translated into drug leads. We discuss the advantages of using peptides as therapeutics to target intracellular protein-protein interactions, chemical strategies to generate macrocyclic peptides that are resistant to proteolytic enzymes, high-throughput screening approaches to identify peptides that have high affinity for therapeutic targets, strategies that permit these peptides to cross cell membranes and so reach intracellular targets, and the importance of investigating their mode-of-action in guiding the development of novel therapeutics.

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

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.

The fecal immunochemical test (fit): Selected aspects regarding its effectiveness for colorectal cancer screening in Quebec City.

Background And Aims: FIT's value has been ascertained across Canada and worldwide, but still needs to be assessed within the province of Quebec. There also remains a gap between formal indications for FIT, and its actual use in clinical practice. This research aims to evaluate some aspects of FIT's effectiveness in our setting, and its application by prescribers.

Development of cell-penetrating peptide-based drug leads to inhibit MDMX:p53 and MDM2:p53 interactions.

The transcription factor p53 has a tumor suppressor role in leading damaged cells to apoptosis. Its activity is regulated/inhibited in healthy cells by the proteins MDM2 and MDMX. Overexpression of MDM2 and/or MDMX in cancer cells inactivates p53, facilitating tumor development.

Impact of cytolysis following transarterial chemoembolization for hepatocellular carcinoma.

Background Aims: Transarterial chemoembolization (TACE) is increasingly used as a treatment of hepatocellular carcinoma. Cytolysis, which may occur within days following the procedure is due to either necrosis of the tumour or of the non-tumoral parenchyma. Therefore it may influence either tumour response or liver function or both.

Acute esophageal necrosis and low-flow state.

Acute esophageal necrosis (AEN), also called black esophagus, is quite exceptional. Endoscopic findings show circumferential black discolouration of the esophagus with or without exudates. The etiology of AEN is presently unknown and is assumed to be multifactorial.