Posted on Apr 09, 2018, 2 a.m.
Synthetic molecules can not only mimic structures of their biological models they can also take on their functions and can successfully compete with them as artificial DNA sequencing now shows, as published in Nature Chemistry.
Backbones of these molecules are referred to as foldamers because much like origami patterns the can adopt predictable shapes which can be easily modified. Scientists have now successfully synthesized a helical molecule which mimics surface features of DNA double helix so closely that bona fide DNA binding proteins interact with it.
This new study shows the synthetic compound is capable of inhibiting activities of several DNA processing enzymes including integrase which is used by HIV to insert its genome into host cells. Successful demonstration of efficacy of the synthetic DNA mimic may lead to adopting new approaches in the treatment of AIDS and other retroviral diseases.
Building on 2 previous studies developing a pattern of binding interactions to enable synthetic molecules to assume stable forms; and investigating conditions which allow synthetic helix to append to natural proteins during synthesis by cellular ribosomes, this study introduces synthetic molecules which fold into helical structures which mimic surface features of DNA double helix, and precise shape can be altered in modular fashion by attachment of substituents, which enables experimenters to imitate in detail shapes of natural DNA double helix position of negative charges so convincingly it acts as decoy for 2 DNA binding enzymes including HIV integrase.
Whether or not the foldamer can effectively compete for enzymes with normal DNA substrates presence is the question. If enzymes still bind to it under competitive conditions it would make the mimic a better binder than the natural DNA. The study has demonstrated that HIV integrase binds more strongly to the mimic. Designed initially to resemble DNA the foldamer owes much of its useful oroerties to features which differentiate it from natural DNA.
Nature of the foldamer design makes structures of the artificial DNA mimics altering applied readily, which enables a vast range of variants able to be produced using the same basic platform. The team focused on enzymes generically capable of binding to DNA regardless of base sequence. It may be possible to use this approach to develop DNA mimics to block actions of many DNA binding proteins whose function depend on recognition of specific nucleotide sequences.
Materials provided by Ludwig-Maximilians-Universität München.
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Krzysztof Ziach, Céline Chollet, Vincent Parissi, Panchami Prabhakaran, Mathieu Marchivie, Valentina Corvaglia, Partha Pratim Bose, Katta Laxmi-Reddy, Frédéric Godde, Jean-Marie Schmitter, Stéphane Chaignepain, Philippe Pourquier & Ivan Huc. Single helically folded aromatic oligoamides that mimic the charge surface of double-stranded B-DNA. Nature Chemistry, 2018 DOI: 10.1038/s41557-018-0018-7