X-ray insights: Anti-inflammatory drugs

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  • Published: May 1, 2015
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: X-ray insights: Anti-inflammatory drugs

Mirror, mirror

Structure of the Spiegelmer NOX-E36 bound to its target protein CCL2. Credit: Dominik Oberthür/CFEL

A new study at DESY, Deutsches Elektronen-Synchrotron, has investigated the detailed structures of two promising anti-inflammatory drug candidates. The work helps explain the mode of action of these substances which have already been entered into clinical trials.

The DESY ultra bright X-ray source PETRA III, has allowed scientists to reveal the three-dimensional structure of two promising drug candidates from the new group of compounds that go by the tradename "Spiegelmers" (Spiegel being German for mirror). The structures offer several new insights into the compounds' mode of action, according to researchers from the Universities of Hamburg, Germany and Aarhus in Denmark and their colleagues at Berlin biotechnology company NOXXON.

Spiegelmers are a relatively new group of pharmaceutical substances, they are composed of the same building blocks as the nucleic acids RNA and DNA and as such are related to the artificial RNA or DNA molecules known as aptamers. Aptamers have biocompatibility and can be designed to bond to certain proteins with high specificity, acting as inhibitors of those proteins. One example of an aptamer has been used marketed since 2006 in the treatment of age-related macular degeneration AMD.

Free laser

Free-roaming RNA and DNA molecules are quickly degraded by enzymes in the body, which limits somewhat the uses of aptamers as pharmaceuticals. However, most biomolecules have a non-superimposable mirror image, their enantiomer, that will not be a substrate for degrading enzymes. Natural nucleic acids exist in the D form, while proteins are always of the L form in the body. If an artificial aptamer is constructed as a non-natural mirror image, L form - a mirror aptamer, or Spiegelmer - it should not be degraded by enzymes but can nevertheless interact with other biomolecules, as team member Christian Betzel from the University of Hamburg explains.

Spiegelmers have identified and optimised in the laboratory. "However, exact structure data of Spiegelmers have not been available until now,” explains Dominik Oberthür from the Center for Free-Electron Laser Science CFEL. Having the precise structure of a Spiegelmer and its binding site at the target protein in hand allows the researchers to model its mode of action with a view to optimising the putative drug still further.

A NOXXON effect

Betzel's team has analysed Spiegelmer NOX-E36. This drug blocks the protein CCL2, one that is involved in several inflammatory disease processes in the body. “If you target an inflammatory protein with a Spiegelmer, you have a good chance to tone down the inflammation in the body,” Betzel explains. NOX-E36 has already been successfully tested in a phase IIa clinical trial with patients. Laure Yatime of the University of Aarhus and colleagues in parallel work have solved the structure of a second Spiegelmer, NOX-D20, which binds to the protein C5a another that is involved in many inflammatory processes and the activity of which is associated with organ damage. Both papers were published in Nature Communications.

The X-ray data provided structural resolution for both Spiegelmers of 0.2 nanometres. “I am delighted to finally have a high resolution visualization of the remarkable shapes of two Spiegelmer drug candidates,” NOXXON founder and CSO Sven Klussmann says. “The structural data not only provide the first look at the unusual interaction of a mirror-image oligonucleotide with a natural protein but also deepens our understanding of the two molecules’ mode of action.”

Related Links

Nature Commun 2015, online: "Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2"

Nature Commun 2015, online: "Structural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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