Cell-Permeable Bicyclic Peptide Inhibitors against Intracellular Proteins

Abstract

Cyclic peptides have great potential as therapeutic agents and research tools but are generally impermeable to the cell membrane. Fusion of cyclic peptides with a cyclic cell-penetrating peptide produces bicyclic peptides that are cell-permeable and retain the ability to recognize specific intracellular targets. Application of this strategy to protein tyrosine phosphatase 1B and a peptidyl-prolyl cis−trans isomerase (Pin1) isomerase resulted in potent, selective, proteolytically stable, and biologically active inhibitors against the enzymes.

One-Bead–Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2

“…The binding affinity of the lead compound to the GST protein ( K d ) was obtained by incubating 50 nM FITC labeled AApeptide in GST ranging from 0.3125 to 55 μ M. Dissociation constants ( K d ) were determined by plotting the fluorescence anisotropy values as a function of protein concentration, and the plots were fitted to the following equation (Figures S7 and S8). 37 …”

Intracellular Delivery of Peptidyl Ligands by Reversible Cyclization: Discovery of a PDZ Domain Inhibitor that Rescues CFTR Activity

“…[3-5] Biologically active cyclic peptides can be delivered into the cytosol and nucleus of mammalian cells by incorporating into them these short sequence motifs. [3,4,6] However, in many circumstances, binding to a molecular target (e.g., PDZ [7,8] and BIR domains [9] ) requires that the peptidyl ligand exist in an extended conformation (e.g., β-strand) and cyclization (or stapling) interferes with target binding. Here we report a potentially general strategy for delivering linear peptides into mammalian cells through reversible, disulfide-mediated cyclization.…”

A fusogenic peptide from a sea urchin fertilization protein promotes intracellular delivery of biomacromolecules by facilitating endosomal escape

“…Although biomacromolecules, such as peptides, enzymes, antibodies and oligonucleotides, have advantages with respect to their unique functions and target specificity compared with small-molecule compounds, biomacromolecules need to be delivered into the cytosol or nucleus for their therapeutic application to directly target intracellular molecules [1][2][3]. Cell-penetrating peptides (CPPs) have so far been employed for the intracellular delivery of various biomacromolecules in the fields of molecular imaging, nucleic acid delivery, peptide/protein delivery and therapeutics [4,5].…”