Abstract
Inhibition of protein–DNA interactions represents an attractive strategy to modulate essential cellular functions. We reported the synthesis of unique oligoamide-based foldamers that adopt single helical conformations and mimic the negatively charged phosphate moieties of B-DNA. These mimics alter the activity of DNA interacting enzymes used as targets for cancer treatment, such as DNA topoisomerase I, and they are cytotoxic only in the presence of a transfection agent. The aim of our study was to improve internalization and selective delivery of these highly charged molecules to cancer cells. For this purpose, we synthesized an antibody-drug conjugate (ADC) using a DNA mimic as a payload to specifically target cancer cells overexpressing HER2. We report the bioconjugation of a 16-mer DNA mimic with trastuzumab and its functional validation in breast and ovarian cancer cells expressing various levels of HER2. Binding of the ADC to HER2 increased with the expression of the receptor. The ADC was internalized into cells and was more efficient than trastuzumab at inhibiting their growth in vitro. These results provide proof of concept that it is possible to site-specifically graft high molecular weight payloads such as DNA mimics onto monoclonal antibodies to improve their selective internalization and delivery in cancer cells.
Highlights
Nucleic acids (NAs) are key players in the regulation of most cellular processes
Trastuzumab has been conjugated to highly cytotoxic drugs such as the tubulin polymerization inhibitor emtansine or the DNA topoisomerase I poison deruxtecan, leading respectively to the two antibody-drug conjugate (ADC), ado-trastuzumab emtansine (T-DM1 or Kadcyla® ) and famtrastuzumab deruxtecan-nxki (DS-8201a or Enhertu® ), that are approved by the FDA
HER2, fluorescence was strictly localized at the cell surface est membrane levels of HER2, fluorescence was strictly localized at the cell surface whereas whereas small intracellular of fluorescence be detected when wereat small intracellular patches patches of fluorescence could becould detected when cells werecells treated treated at 37°C, which indicated an internalization of the Similarwere results were ob37◦ C, which indicated an internalization of the ADC
Summary
Nucleic acids (NAs) are key players in the regulation of most cellular processes. This role relies on both the ability of two complementary NA strands to hybridize through Watson–Crick purine/pyrimidine base-pairing, and on NA interactions with various proteins via specific features of their surfaces, including shape, charge distribution or groove width, as defined by the base sequence. Disruption of NA base pairing or NA-protein interactions may have drastic consequences on cell fate, justifying high interest for synthetic NA mimics that could alter such processes for diagnostic purposes or therapeutic applications. Regarding the inhibition of nucleic acid-protein interactions, several reports showed that it can be achieved with small molecules such as DNA ligands [5,6,7], ‘interfacial’ inhibitors targeting specific DNA-protein. The de novo design and synthesis of molecules (e.g., peptides) that mimic
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