###### 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. D 2021 25 June 202  
complexes [8; 9] or with oligodeoxynucleotide decoys targeting specific transcription factors [10; 11; 12]. The de novo design and synthesis of molecules (e.g., peptides) that mimic DNA surface features is another attractive strategy to interfere with DNA-protein interactions [13]. It is inspired by the description of more than a dozen of naturally occurring DNA mimic proteins that impair the biological functions of prokaryotic or eukaryotic enzymes involved in various cellular processes, presumably via a competitive inhibition of their interaction with NAs [14]. Recently, we have reported the synthesis of unique oligoamide-based foldamers that adopt single helical conformations and mimic the array of negatively charged phosphate moieties in double-stranded B-DNA. We found that these DNA mimics could alter the function of DNA interacting enzymes, such as Topoisomerase I and HIV-1 integrase in vitro [15]. We further demonstrated that, depending on the spatial distribution and the nature of anionic side chains on the foldamers, it was possible to inhibit the activity of DNA-interacting enzymes in a selective manner [16]. We also showed that these foldamers could inhibit the growth of cancer cells. However, this effect could only be observed when delivery was carried out by a transfection agent [15]. Indeed, the polyanionic nature of the DNA mimics and their poor lipophilicity--in other words their resemblance to DNA--precluded their entry into cells, pointing towards the need for derivatives with enhanced cell penetration ability. Another issue resides in the possibility to selectively target cancer cells as DNA mimics can also inhibit the growth of normal cells (unpublished observations). These data led us to consider several vectorization options of DNA mimics, including the development of an antibody-drug conjugate (ADC). ADCs result from the grafting of several molecules (e.g., cytotoxic agents) onto a monoclonal antibody targeting a specific internalizing antigen that is overexpressed at the surface of cancer cells. The design, synthesis and development of ADCs have made substantial progress within the past ten years [17]. Original payloads exhibiting new mechanisms of action, site-specific bioconjugation technologies, improved linkers [18; 19] allowing for a better control of the drug-to-antibody ratio (DAR), optimization of ADC internalization and payload release [20; 21] led to second and third generation ADCs with a more effective therapeutic index.