Chemically modified nucleic acids, commonly in the form of oligonucleotides, are valuable tools in chemical biology for gene regulation, editing, biological inhibition, and sensing. 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, as demonstrated in the above figure. The benefits of our post-synthetic approach are numerous: it is straightforward in procedure, mild in conditions, efficient in reaction, and versatile in chemistry.
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. Two nucleic acids, DNAzyme and guide RNA (gRNA), are responsible for recognizing target mRNA and genes in these processes. To achieve more precise and efficient gene regulation and editing, chemically modified forms of DNAzyme and gRNA are gaining attention due to their potentially lower off-target effects compared to their native counterparts.
We are developing gene regulation and editing tools that can be triggered by stimuli-responsive groups, such as those activated by reactive oxygen species (ROS) and UV/Vis light irradiation. By modifying DNAzyme and gRNA with these groups, we can initiate conditionally controlled gene regulation/editing with high specificity. Furthermore, these tools can record the history of ROS upregulation in genomic DNA over multiple passages, enabling the study of ROS effects on cell fate. This approach has promising applications for understanding the mechanisms of disease and developing targeted therapies.
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 inhibiting and sensing functions that extend well beyond those of their native counterparts due to the diverse functional groups they can possess.
We are utilizing sulfur chemistry to modify aptamers, DNAzymes, and long RNA with interesting chemical groups, creating new inhibitors and sensors with exciting performance capabilities to address current challenges in therapeutics and diagnosis. Our approach offers an opportunity to develop nucleic acid-based inhibitors and sensors with enhanced specificity and sensitivity. This research has promising implications for advancing the fields of personalized medicine, drug discovery, and disease diagnosis.