Berlin, Germany and Boston, USA - 23 April 2015 - NOXXON Pharma announced today the publication of two new studies in Nature Communications, entitled:
- Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2 (link to the article on
- Structural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer (link to the article on
Scientists from the University of Hamburg, Germany, and Aarhus University, Denmark, have solved the crystal structures of two Spiegelmers (NOX-E36 and NOX-D20) bound to their respective biological targets: the pro-inflammatory chemokine CCL2 (also known as monocyte chemoattractant protein 1, MCP-1) and the complement component C5a. Built on a backbone of mirror-image RNA or DNA, Spiegelmers belong to a class of drugs known as aptamers which can bind to molecular targets with high affinity and specificity in order to modulate the biological function of that target. These are the first crystal structures ever published of Spiegelmers bound to targets.

Sven Klussmann, founder and CSO of NOXXON Pharma, and also co-author on both articles commented: "I am delighted to finally have a high resolution visualization of the remarkable shapes of two Spiegelmer® product candidates. 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."

Dr. Dominik Oberthür from the University of Hamburg and colleagues describe the structure of the Spiegelmer® NOX-E36 bound to the pro-inflammatory chemokine CCL2. CCL2 is upregulated under diabetic conditions and implicated in inflammation, such as that present in many tissues and organs in diabetic patients, including the kidney. CCL2, like other chemokines has two types of binding sites: one that binds specifically with receptors to trigger signaling within cells, and a second that binds non-specifically to cell surfaces to allow for the formation of a concentration gradient that migrating cells with the appropriate receptors can follow. The authors revealed that NOX-E36 covers both sites on CCL2 when it binds, suggesting a dual mechanism of action on this chemokine.

Dr. Laure Yatime from Aarhus University and colleagues describe the structure of the Spiegelmer® NOX-D20, a precursor Spiegelmer® to current development candidate NOX-D21, in complex with C5a. C5a is a chemoattractant for immune cells, stimulates the expression of pro-inflammatory cytokines and chemokines, and triggers edema. C5a is believed to lead to organ damage in life-threatening conditions such as severe pneumonia and sepsis. The Spiegelmer® NOX-D20 was found to cover epitopes that are important for C5a receptor binding, providing an explanation for its inhibition of this target.

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