Rare is the biomimetic material that out-performs the natural counterpart it seeks to emulate. However, not only can some compounds mimic their biological models but they can have additional functionality, according to Ivan Huc of Ludwig-Maximilians-Universität München, Germany and his colleagues whose artificial DNA sequence shows.
Writing in the journal Nature Chemistry, the team describes how they have successfully made a helical molecule that mimics surface features of the DNA double helix so closely that natural DNA-binding proteins will interact with it. The synthetic helix can thus inhibit several DNA-processing enzymes, such as the integrase used by the Human Immunodeficiency Virus (HIV) to insert its genome into a host cell. The team's success might lead to a biomimetic approach to treating AIDS and other diseases as well as opening up ways to control and manipulate proteins. [Huc et al Nature Chem (2018); DOI: 10.1038/s41557-018-0018-7]
Previously, the team developed a pattern of binding interactions necessary for synthetic molecules to assume stable forms similar to the helical backbones of proteins. They then worked out the conditions needed to allow the synthetic helices to be appended to natural proteins during synthesis by cellular ribosomes.
"As always in biology, shape determines function," Huc explains. In the new work, the team introduces a synthetic molecule that folds into a helix to mimic the surface of DNA. The team can tweak the precise shape in a modular fashion by attaching different substituents allowing them to mimic specific strands of natural DNA with precision and with particular focus on the negative charges. The mimics are so convincing that they essentially act as a decoy for DNA-binding enzymes, including the aforementioned HIV integrase.
Of course, to be useful the biomimetic foldamer must be able to out-compete the natural DNA substrate. "If the enzymes still bind to the foldamer under competitive conditions, then the mimic must be a better binder than the natural DNA itself," Huc explains. Their experiments shows that this is indeed the case the biomimetic binds more strongly to HIV integrase than the enzymes does to natural DNA. "Although initially designed to resemble DNA, the foldamer owes its most useful and valuable properties to the features that differentiate it from DNA," Huc points out.
The modular nature of their foldamer design means that the researchers can fine tune properties for particular applications. This allows them to create a broad range of variations on the theme using the same synthesis platform. It might be possible to make biomimetic foldamers that can block other DNA-binding proteins.
David Bradley blogs at Sciencebase Science Blog and tweets @sciencebase, he is author of the popular science book "Deceived Wisdom".