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

摘要

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??. 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.