Thiazole orange peptidoconjugates as nucleic acid and cellular probes

Small molecule probes of biological systems are becoming increasingly powerful tools for the elucidation of complex interactions between biomolecules. Due to facile synthetic procedures and the wealth of diversity available from the varied functional groups of amino acid side chains, peptide-based biomimetic compounds are of particular interest. Additionally, because of their likeness to native systems, the information obtained from such probes can be directly related to parent molecules.; Described herein are methods for the development of peptide-based probes, termed peptidoconjugates. A fluorescent DNA intercalator, thiazole orange (TO) was synthetically modified to allow for incorporation at the N terminus of a peptide chain using solid phase synthesis. Peptide-conjugates of various amino acid lengths and composition were synthesized and their interactions with DNA were characterized using a variety of spectroscopic methods. Upon photoexcitation, these molecules were found to initiate a novel oxygen dependent amino acid-promoted reaction that lead to DNA cleavage. Additionally, TO-peptidoconjugates were found to permeate the plasma membrane of cultured cells and could be specifically localized to intracellular destinations based on the attached peptide sequence. Once inside the cell, these molecules could be activated with light to initiate apoptosis. Such probes will be of immense importance to the study of organelle-specific oxidative stress response and have potential applications in photodynamic therapy.