Structural requirements of mono- and multivalent L-selectin blocking aptamers for enhanced receptor inhibition in vitro and in vivo
| Autor: | Rudolf Tauber, Sebastian B. Riese, Jens Dernedde, Christian Kuehne, Konrad Buscher, Sven Enders |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.drug_class Aptamer Oligonucleotides Biomedical Engineering Pharmaceutical Science Medicine (miscellaneous) Bioengineering Plasma protein binding Ligands Monoclonal antibody 03 medical and health sciences In vivo Cell Adhesion Leukocytes medicine Humans General Materials Science L-Selectin Cell adhesion Inflammation 030102 biochemistry & molecular biology Chemistry Oligonucleotide Aptamers Nucleotide Healthy Volunteers Extravasation 030104 developmental biology Biochemistry Blood Buffy Coat Biophysics Molecular Medicine P-selectin glycoprotein ligand-1 Protein Binding |
| Zdroj: | Nanomedicine: Nanotechnology, Biology and Medicine. 12:901-908 |
| ISSN: | 1549-9634 |
| Popis: | L-selectin mediates extravasation of leukocytes from blood into the surrounding tissue during inflammation and is therefore a therapeutical target in certain overwhelming immune reactions. In this study, we characterized an L-selectin specific blocking DNA aptamer with respect to nucleotide composition and target binding. Introduction of deletions and nucleotide exchanges resulted in an optimized DNA sequence but preservation of the IC 50 in the low nanomolar range. The inhibitory potential was significantly increased when the aptamer was displayed as a di- and trimer connected via appropriate linker length. Similar to monoclonal antibodies, trimer yielded picomolar IC 50 values in a competitive binding assay. In comparison to the monovalent aptamer, the trivalent assembly reduced PBMC interactions to L-selectin ligands 90-fold under shear and exerted superior inhibition of PBMC rolling in vivo . In conclusion, our work demonstrates the feasibility of optimizing aptamer sequences and shows that multivalent ligand presentation enables superior adhesion receptor targeting. From the Clinical Editor During inflammation, leukocytes extravasate from blood vessels under chemotaxic signals. The presence of L-selectin on endothelium acts as a mediator for the extravasation process. In this study, the authors investigated an L-selectin specific blocking DNA aptamer in various forms, as inhibitors to leukocyte binding and extravasation. This new approach confirmed the potential use of aptamers in clinical setting. |
| Databáze: | OpenAIRE |
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