Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2

Dominik Oberthür, John Achenbach, Azat Gabdulkhakov, Klaus Buchner, Christian Maasch, Sven Falke, Dirk Rehders, Sven Klussmann () and Christian Betzel ()
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Dominik Oberthür: Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg
John Achenbach: NOXXON Pharma AG
Azat Gabdulkhakov: Institute of Protein Research, RAS, Pushchino
Klaus Buchner: NOXXON Pharma AG
Christian Maasch: NOXXON Pharma AG
Sven Falke: Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg
Dirk Rehders: Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg
Sven Klussmann: NOXXON Pharma AG
Christian Betzel: Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract We report the crystal structure of a 40mer mirror-image RNA oligonucleotide completely built from nucleotides of the non-natural L-chirality in complex with the pro-inflammatory chemokine L-CLL2 (monocyte chemoattractant protein-1), a natural protein composed of regular L-amino acids. The L-oligonucleotide is an L-aptamer (a Spiegelmer) identified to bind L-CCL2 with high affinity, thereby neutralizing the chemokine’s activity. CCL2 plays a key role in attracting and positioning monocytes; its overexpression in several inflammatory diseases makes CCL2 an interesting pharmacological target. The PEGylated form of the L-aptamer, NOX-E36 (emapticap pegol), already showed promising efficacy in clinical Phase II studies conducted in diabetic nephropathy patients. The structure of the L-oligonucleotide·L-protein complex was solved and refined to 2.05 Å. It unveils the L-aptamer’s intramolecular contacts and permits a detailed analysis of its structure–function relationship. Furthermore, the analysis of the intermolecular drug–target interactions reveals insight into the selectivity of the L-aptamer for certain related chemokines.

Date: 2015
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DOI: 10.1038/ncomms7923

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