DNA Mimics that Inhibit DNA-Protein Interactions May Lead to Novel Therapeutics

DNA, the central molecule of life, carries genetic information organized in the two complementary strands of its double helix. In order for this genetic information to be read and executed, or on the contrary to prevent or regulate its expression, a number of proteins interact with DNA, for example by “binding” to the negative charges located on its surface. This is the case for HIV integrase, which enables the insertion of the viral DNA into human DNA and topoisomerase, an enzyme that acts to release tensions within the DNA molecule when it is supercoiled.

Scientists from the CNRS, Inserm, and Bordeaux University say they have developed an artificial sequence mimicking the surface features of DNA for the first time. This molecule is able to inhibit the activity of several DNA-binding enzymes, including HIV integrase, which is used by HIV to insert its genome into that of its host cell.

The study (“Single Helically Folded Aromatic Oligoamides That Mimic the Charge Surface of Double-Stranded B-DNA”) is published in Nature Chemistry and it paves the way for new pharmacological tools based on inhibiting DNA–protein interactions, according to the researchers.

“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,” write the investigators.

“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.”

The team successfully synthesized helical molecules that precisely imitate the surface features of DNA’s double helix and notably the position of its negative charges. These molecules are derived from aromatic foldamers, synthetic objects with a strong propensity to adopt folded conformations, in this case, a single helix.

The imitation is so convincing that these foldamers trick certain proteins that would normally bind to DNA, including topoisomerase and HIV integrase, explain the researchers, who demonstrate that the synthetic mimics make better ligands for these enzymes than natural DNA, even at weak concentrations of foldamers. It seems that this efficacy is due to subtle differences between their structure and that of natural DNA.

These DNA mimics open the door for as yet unexplored approaches to inhibiting DNA–protein interactions, which could, in the future, lead to new medicines, add the scientists.