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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Sell, Simone Kolodziejski, Pawel Vater, Axel Buchner, Klaus Pruszynska-oszmalek, Ewa Strowski, Mathias Z. Maasch, Christian Kaczmarek, Przemyslaw Nowak, Krzysztof W. Klussmann, Sven Purschke, Werner G. |
| Description | Author Affiliation: Vater A ( NOXXON Pharma AG, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.) |
| Abstract | Excessive secretion of glucagon, a functional insulin antagonist, significantly contributes to hyperglycemia in type 1 and type 2 diabetes. Accordingly, immunoneutralization of glucagon or genetic deletion of the glucagon receptor improved glucose homeostasis in animal models of diabetes. Despite this strong evidence, agents that selectively interfere with endogenous glucagon have not been implemented in clinical practice yet. We report the discovery of mirror-image DNA-aptamers (Spiegelmer®) that bind and inhibit glucagon. The affinity of the best binding DNA oligonucleotide was remarkably increased (>25-fold) by the introduction of oxygen atoms at selected 2′-positions through deoxyribo- to ribonucleotide exchanges resulting in a mixed DNA/RNA-Spiegelmer (NOX-G15) that binds glucagon with a $K_{d}$ of 3 nm. NOX-G15 shows no cross-reactivity with related peptides such as glucagon-like peptide-1, glucagon-like peptide-2, gastric-inhibitory peptide, and prepro-vasoactive intestinal peptide. In vitro, NOX-G15 inhibits glucagon-stimulated cAMP production in CHO cells overexpressing the human glucagon receptor with an $IC_{50}$ of 3.4 nm. A single injection of NOX-G15 ameliorated glucose excursions in intraperitoneal glucose tolerance tests in mice with streptozotocin-induced (type 1) diabetes and in a non-genetic mouse model of type 2 diabetes. In conclusion, the data suggest NOX-G15 as a therapeutic candidate with the potential to acutely attenuate hyperglycemia in type 1 and type 2 diabetes. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 29 |
| Volume Number | 288 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2013-07-19 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Aptamers, Nucleotide Pharmacology Diabetes Mellitus, Type 1 Blood Diabetes Mellitus, Type 2 Glucagon Antagonists & Inhibitors RNA Metabolism Animals Pharmacokinetics Therapeutic Use Blood Glucose Body Weight Drug Effects CHO Cells Cricetinae Cricetulus Cyclic AMP Biosynthesis Drug Therapy Disease Models, Animal Fasting Glucose Tolerance Test Kinetics Mice Mice, Inbred BALB C Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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