CpG Oligonucleotides with Modified Termini and Nicked Dumbbell Structure Show Enhanced Immunostimulatory Activity
| Autor: | Alexander H. Dalpke, Klaus Heeg,§, and, Karsten Siegmund, Sukunath Narayanan, Clemens Richert |
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| Rok vydání: | 2003 |
| Předmět: |
Magnetic Resonance Spectroscopy
Ultraviolet Rays Stereochemistry Oligonucleotides Bone Marrow Cells Nitric Oxide Cell Line Photometry Mice Structure-Activity Relationship chemistry.chemical_compound Adjuvants Immunologic Drug Discovery Animals Nucleotide chemistry.chemical_classification Mice Inbred BALB C Interleukin-12 Subunit p40 Interleukin-6 Tumor Necrosis Factor-alpha Oligonucleotide Macrophages Cationic polymerization Chemical modification Stereoisomerism Dendritic Cells Interleukin-12 Solutions Protein Subunits chemistry Duplex (building) Phosphodiester bond Molecular Medicine CpG Islands Dumbbell Thymidine |
| Zdroj: | Journal of Medicinal Chemistry. 46:5031-5044 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm030902l |
| Popis: | A series of 21 phosphodiester oligodeoxyribonucleotides containing the core sequence 5'-GACGTT-3' or related control sequences were prepared and tested for their immunostimulatory effect on murine macrophages. The range of structural modifications tested included substituents at 3'- or 5'-termini, N3-methylation of thymidine residues, and hexaethylene glycol linkers favoring nicked or cyclic dumbbell duplexes. Lipophilic and cationic substituents at the termini failed to increase the release of TNF-alpha and nitric oxide, but two new types of modification were found that enhance the stimulation of RAW264.7 macrophages. One is the substitution of the 5'-terminal hydroxyl group with an amino group, and the other is the introduction of linkers favoring nicked duplexes. Even for sequences without linkers, UV-melting analysis and two-dimensional NMR showed that the core sequence 5'-GACGTT-3' readily forms a duplex. The cyclic derivative of the most active nicked dumbbell sequence is inactive, however. Together these results suggest a recognition of both the 5'-terminus and the core of the CpG oligonucleotides by the putative receptor(s) and provide an entry into a class of modified oligonucleotides whose activity rivals that of phosphorothioates, but consists of synthetic compounds that are single stereoisomers. |
| Databáze: | OpenAIRE |
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