Abstract: The method of the present invention employs a hybrid reagent comprising a first portion (i.e., a cell-targeting portion) which binds to cell surfaces coupled to a second portion (i.e., a toxin-binding portion) which binds to, or has bound to it, an endosomally active domain of DT and releases the endosomally active domain of DT in response to the low pH in endosomal vesicles of cells. Thus, the second portion of the hybrid reagent binds an endosomally active domain directly (e.g., an antibody which binds to all or a portion of the T domain of DT) or indirectly (e.g., an antibody which binds to the R domain of a moiety in which the R domain of DT is coupled to the T domain of DT). A second endosomally active domain of DT, which is different from the first endosomally active domain of DT, is delivered to the same endosomal vesicles separately. The independent endosomally active domains of DT are not toxic to cells until they meet within the endosomes.

Abstract: Disclosed herein is a cell containing a modified peptide. More specifically, the N-terminal amino acid residue of the peptide is modified by the addition of an aryl ketone group which, when contacted with an appropriate substrate, and exposed to light having a wavelength of about 330 nm or greater, results in the covalent bonding of the peptide to the substrate by a C--H insertion dominant mechanism. In preferred, embodiments, the aryl ketone is a benzophenone moiety. The peptide can be designed to specifically bind to a protein of interest in the cell. The cell is then contacted with light having a wavelength of greater than about 330 nm to bind the peptide covalently to the binding site on the intracellular protein of interest. In this way, the modified peptide can be used to specifically and irreversibly block a binding site on an intracellular protein of interest.