Chemically modified nucleic acids, commonly in the form of oligonucleotides, are powerful tools in chemical biology. However, functionalizing nucleic acids with artificial modifications that are challenging for solid-phase synthesis remains difficult.
We are developing post-synthetic methods based on sulfur chemistry to incorporate a broad range of functional groups of interest into nucleic acids. Examples of these methods include phosphorothioate and 4-thiouracil chemistry. The benefits of these post-synthetic approaches are numerous. They are straightforward in procedure, mild in condition, efficient in reaction, and versatile in chemistry.
ACS Chem. Biol. 2016, 11, 444
Chem. Commun. 2019, 55, 13096
Gene regulation and editing at the mRNA and DNA levels, respectively, are state-of-the-art strategies for understanding and manipulating biology and treating genetic diseases. Deoxyribozyme (DNAzyme) and guide RNA (gRNA) are efficient in recognizing mRNA and genomic DNA, respectively.
We are developing gene regulation and editing tools that can be conditionally triggered by stimuli-responsive groups, such as those activated by reactive oxygen species (ROS) and UV/Vis light irradiation. These more precise gene regulation and editing tools are enabled by the chemically modified DNAzyme and gRNA based on the sulfur chemistry.
Angew. Chem. Int. Ed. 2019, 58, 14167
Chem. Sci., 2021, 12, 9934
Biological inhibitors and sensors are valuable tools for therapeutics and diagnosis. Nucleic acids, such as functional DNA and RNA, can serve as highly efficient biological inhibitors and sensors. Chemically modified nucleic acids can acquire functions well beyond those of their native counterparts due to expanded chemistry.
We are utilizing sulfur chemistry to modify aptamers, DNAzymes, and long RNA with interesting chemical groups, creating new inhibitors and sensors with exciting capabilities to address current challenges in therapeutics and diagnosis. We develop these artificial sequences by both rational design and directed evolution strategies.
Bioconjug. Chem., 2022, 33, 164
Nat. Chem., 2023, DOI: 10.1038/s41557-023-01304-z