Bile Acid Conjugated DNA Chimera that Conditionally Inhibits Carbonic Anhydrase-II in the Presence of MicroRNA-21
| Autor: | Xiaozhu Chu, Cooper H. Battle, Janarthanan Jayawickramarajah, Gyan H. Aryal, Madhusoodanan Mottamal, Nan Zhang |
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| Rok vydání: | 2015 |
| Předmět: |
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Molecular Lithocholic acid Carbonic anhydrase II Biomedical Engineering Pharmaceutical Science Bioengineering Carbonic Anhydrase II Article Bile Acids and Salts chemistry.chemical_compound Structure-Activity Relationship Catalytic Domain microRNA Humans Carbonic Anhydrase Inhibitors Pharmacology chemistry.chemical_classification biology Chemistry Organic Chemistry Active site DNA Prodrug MicroRNAs Enzyme Biochemistry Cancer cell biology.protein Biotechnology |
| Zdroj: | Bioconjugate chemistry. 26(8) |
| ISSN: | 1520-4812 |
| Popis: | In order to tackle the issue of systemic toxicity in chemotherapy, there is a need to develop novel mechanisms for the activation of protein inhibitors using biomarkers over-expressed in cancer cells. Many current strategies focus on using cancer associated enzymes as a triggering agent for prodrugs. Herein, we detail an alternative approach that harnesses a microRNA (miR-21) that is overexpressed in cancers as the trigger that activates an inhibitor of human carbonic anhydrase-II (hCA-II). Specifically, we have developed a DNA-small molecule chimera (DC) composed of an hCA-II binding lithocholic acid amide (LAA) head-group that can transition from a rigid duplex state (that does not bind appreciably to hCA) to a single stranded conformation via a miR-21 trigger. The activated single-stranded DC can project the LAA head-group into the hCA-II active site and is a robust hCA-II inhibitor (Ki of 3.12 μM). This work may spur research into developing new classes of cancer selective protein inhibitors. |
| Databáze: | OpenAIRE |
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