Single helically folded aromatic oligoamides that mimic the charge surface of double-stranded B-DNA

Numerous essential biomolecular processes require the recognition of DNA surface features by proteins. Molecules mimicking these features could potentially act as decoys and interfere with pharmacologically or therapeutically relevant protein–DNA interactions. Although naturally occurring DNA-mimicking proteins have been described, synthetic tunable molecules that mimic the charge surface of double-stranded DNA are not known. Here, we report the design, synthesis and structural characterization of aromatic oligoamides that fold into single helical conformations and display a double helical array of negatively charged residues in positions that match the phosphate moieties in B-DNA. These molecules were able to inhibit several enzymes possessing non-sequence-selective DNA-binding properties, including topoisomerase 1 and HIV-1 integrase, presumably through specific foldamer–protein interactions, whereas sequence-selective enzymes were not inhibited. Such modular and synthetically accessible DNA mimics provide a versatile platform to design novel inhibitors of protein–DNA interactions. Molecules that mimic the charge surface of B-DNA could enable the inhibition of DNA processive enzymes. Now, helically folded aromatic oligoamide scaffolds have been synthesized that display anions at positions similar to that of B-DNA phosphates. These foldamer mimics can recognize some DNA binding proteins and inhibit enzymes such as HIV integrase and topoisomerase 1.