Research

Next-Generation RNA Therapeutics

RNA is the most versatile biomolecule in cells, regulating virtually every aspect of living processes. Its therapeutic potential however has long been underestimated until the emergence of Covid-19 mRNA vaccine. Naturally occurring/derived chemical modifications of RNA (e.g., Ψ, N1mΨ, m5C, m5U etc.) are known to stabilize RNA and reduce immunogenicity. We will develop new chemistry to design new-to-nature RNA mimetics to further improve RNA stability, protein translation efficiency, and reduce immunogenicity. Such RNA mimetics will be applied in mRNA vaccine (for cancer immunotherapy and viral infection), protein-replacement therapy, miRNA, siRNA, and gene editing (CRISPR).

Reprogram RNA with Small-Molecule

Undruggability issues of most protein targets have limited our ability to treat most notorious human diseases. Targeting RNA with small molecules thereby has become an attractive alternative. However, current methods primarily focus on using short synthetic RNAs under in vitro conditions, overlooking RNA strucutural diferences (i.e., in vitro vs. in cell) and potential binding competitions from proteins. We will develop general platforms to identify RNA-binding small molecules in cells. Structurally optimized molecules will be used to modulate RNA function and fate for therapeutic benefits.

Enzyme-Like DNA Catalyst Design

There is a gap between small-molecule catalysts (e.g., transition-metal catalysis or organocatalysis) and enzymes (i.e., natural or evolved) where optimal generalizability and specificity of a catalyst might be realized. Generally, small-molecule catalysts offer new-to-nature reactivities and good generalizability, whereas enzymes are much more specific and efficient on certain reactions (especially biological reactions). We will combine the features of these two types of catalysts by building small-molecule catalysts on structurally chiral and programmable DNA scaffolds in order to achieve unsolved reactivity and selectivity in catalysis ideally in aqueous media.