Multivalent Aptamer‐Functionalized Single‐Strand RNA Origami as Effective, Target‐Specific Anticoagulants with Corresponding Reversal Agents
| Autor: | Abhichart Krissanaprasit, Daniel M. Dupont, Carson M Key, Emily Mihalko, Sahil Pontula, Ebbe Sloth Andersen, Kristen Froehlich, Ashley C. Brown, Jørgen Kjems, Thomas H. LaBean |
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| Rok vydání: | 2021 |
| Předmět: |
RNA nanotechnology
anticoagulants medicine.drug_class Aptamer aptamers Biomedical Engineering Pharmaceutical Science 02 engineering and technology 010402 general chemistry 01 natural sciences Biomaterials chemistry.chemical_compound Thrombin medicine Blood Coagulation Nuclease Peptide nucleic acid biology Anticoagulant Anticoagulants RNA RNA origami Aptamers Nucleotide direct thrombin inhibitors 021001 nanoscience & nanotechnology 0104 chemical sciences nucleic acids chemistry Biochemistry biology.protein Nucleic acid reversal agents 0210 nano-technology DNA medicine.drug |
| Zdroj: | Advanced Healthcare Materials Krissanaprasit, A, Key, C M, Froehlich, K, Pontula, S, Mihalko, E, Dupont, D M, Andersen, E S, Kjems, J, Brown, A C & LaBean, T H 2021, ' Multivalent Aptamer-Functionalized Single-Strand RNA Origami as Effective, Target-Specific Anticoagulants with Corresponding Reversal Agents ', Advanced Healthcare Materials, vol. 10, no. 11, 2001826 . https://doi.org/10.1002/adhm.202001826 |
| ISSN: | 2192-2659 2192-2640 |
| DOI: | 10.1002/adhm.202001826 |
| Popis: | Anticoagulants are commonly utilized during surgeries and to treat thrombotic diseases like stroke and deep vein thrombosis. However, conventional anticoagulants have serious side-effects, narrow therapeutic windows, and lack safe reversal agents (antidotes). Here, an alternative RNA origami displaying RNA aptamers as target-specific anticoagulant is described. Improved design and construction techniques for self-folding, single-molecule RNA origami as a platform for displaying pre-selected RNA aptamers with precise orientational and spatial control are reported. Nuclease resistance is added using 2'-fluoro-modified pyrimidines during in vitro transcription. When four aptamers are displayed on the RNA origami platform, the measured thrombin inhibition and anticoagulation activity is higher than observed for free aptamers, ssRNA-linked RNA aptamers, and RNA origami displaying fewer aptamers. Importantly, thrombin inhibition is immediately switched off by addition of specific reversal agents. Results for single-stranded DNA (ssDNA) and single-stranded peptide nucleic acid (PNA) antidotes show restoration of 63% and 95% coagulation activity, respectively. To demonstrate potential for practical, long-term storage for clinical use, RNA origami is freeze-dried, and stored at room temperature. Freshly produced and freeze-dried RNA show identical levels of activity in coagulation assays. Compared to current commercial intravenous anticoagulants, RNA origami-based molecules show promise as safer alternatives with rapid activity switching for future therapeutic applications. |
| Databáze: | OpenAIRE |
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