Evolution of Functionally Enhanced α-l-Threofuranosyl Nucleic Acid Aptamers
| Autor: | Cailen M McCloskey, Ryan Poplin, Nicholas Chim, Ivan Grubisic, Qingfeng Li, Esau Medina, John C. Chaput, Eric J. Yik, Arlene K. Ngor, Lance Co Ting Keh |
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| Rok vydání: | 2021 |
| Předmět: |
Chemistry
Polymers Aptamer Biomedical Engineering Threose nucleic acid Proteins General Medicine Aptamers Nucleotide Biochemistry Genetics and Molecular Biology (miscellaneous) Chemical space Receptor–ligand kinetics Antibodies Kinetics Biochemistry Nucleic Acids Nucleic acid Paratope Tetroses Uracil nucleotide Function (biology) |
| Zdroj: | ACS synthetic biology. 10(11) |
| ISSN: | 2161-5063 |
| Popis: | Synthetic genetic polymers (xeno-nucleic acids, XNAs) have the potential to transition aptamers from laboratory tools to therapeutic agents, but additional functionality is needed to compete with antibodies. Here, we describe the evolution of a biologically stable artificial genetic system composed of α-l-threofuranosyl nucleic acid (TNA) that facilitates the production of backbone- and base-modified aptamers termed "threomers" that function as high quality protein capture reagents. Threomers were discovered against two prototypical protein targets implicated in human diseases through a combination of in vitro selection and next-generation sequencing using uracil nucleotides that are uniformly equipped with aromatic side chains commonly found in the paratope of antibody-antigen crystal structures. Kinetic measurements reveal that the side chain modifications are critical for generating threomers with slow off-rate binding kinetics. These findings expand the chemical space of evolvable non-natural genetic systems to include functional groups that enhance protein target binding by mimicking the structural properties of traditional antibodies. |
| Databáze: | OpenAIRE |
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