Invention of stimulus‐responsive peptide‐bond‐cleaving residue (Spr) and its application to chemical biology tools

Abstract

Elucidation of biological functions of peptides and proteins is essential for understanding peptide/protein-related biological events and developing drugs. Caged peptides and proteins that release a parent active peptide/protein by photo-irradiation have successfully been employed to elucidate the functions. Whereas the usual caged peptide/protein enables conversion of an inactive form to an active form (OFF-to-ON conversion) by photo-induced deprotection, photo-triggered main chain cleavage is reported to be applicable to ON-to-OFF conversion. These peptides and proteins are photo-responsive; however, if peptides and proteins could respond to other stimuli such as disease-related environment or enzymes, their range of application should be widened. To convert the photo-responsive peptide/protein into other stimulus-responsive peptide/protein, quite laborious de novo design and synthesis of the stimulus-responsive unit are required. In this context, we designed a stimulus-responsive peptide-bond-cleaving residue (Spr) in which the stimuli available for the main chain cleavage vary according to the choice of protecting groups on the residue. In this review, design and synthesis of Spr are introduced, and challenges to apply Spr to other fields to enable, for example, functional control, localization control, delivery of cargos, labeling of a protein of interest in living cells, and identification of target proteins of bioactive ligands are discussed. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Elucidating the Therapeutic Potential of Cell-Penetrating Peptides in Human Tenon Fibroblast Cells

“…JTS-1 was designed with an α-helical structure to replace gene therapy viral vectors. 37 The JTS-1 peptide was designed to form a complex with DNA and demonstrated improved transfection in epithelial cell lines. 38 The peptide interacts spontaneously with DNA and disrupts the endosome, allowing for efficient gene transfer.…”

“…To fill this gap in the field of CPP delivery, we investigated the effect of JTS-1 in TF cells. JTS-1 was designed with an α-helical structure to replace gene therapy viral vectors . The JTS-1 peptide was designed to form a complex with DNA and demonstrated improved transfection in epithelial cell lines .…”

Development of Chemical Biology Tools Focusing on Peptide/Amide Bond Cleavage Reaction

“…Because details of the stimulus-responsive amino acid were reported in our recent review, 2) it is only briefly described in this section.…”

“…24) Application of Spr in topics not mentioned in this paper 14,17,18,25,26) are detailed in our recent review. 2)…”

“…I thought that "formation of peptide bond" is Red Ocean, but "cleavage of peptide/amide bond" might be Blue Ocean. 1) I therefore decided to invent peptide/amide bond cleavage-based chemical biology tools for the peptide/protein sciences.…”