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Synthesis of novel modified L-RNA for SELEX of therapeutic aptamers
RNA aptamers, with a high affinity for a variety of molecular ligands, have been identified as promising therapeutic candidates using systematic evolution of ligands by exponential enrichment (SELEX). SELEX-based RNA aptamers have many advantages, such as low immunogenicity and fast in vitro selection process. Scientists have also applied the non-natural diastereomeric L-type RNA aptamer to target small molecule or disease-related RNA motifs. The inherent property of L-type RNA makes it unable to be recognized by native RNase, which greatly enhances stability in physiological conditions. Our lab is trying to introduce functional chemical modifications into the L-RNA through chemical synthesis, thereby enhancing the binding affinity, selectivity and bio-stability of the L-RNA aptamer, and eventually leading to a promising RNA drug candidate. The promising targets of L-RNA based aptamers include cancer related miRNA elements, tRNA fragment and cancer cells.
Mechanistic studies on RNA self-replication in origin of life
According to RNA world hypothesis, the non-enzymatic RNA polymerization is a critical transitional stage between prebiotic chemistry of ribonucleotides and the evolution of ribozyme-catalyzed RNA replication. A detailed, structure-based understanding of how the activated nucleotide substrates react with RNA primer-template duplexes will inform on the mechanism of the replication. Recently, it has been revealed that the non-enzymatic RNA polymerization is potentially driven by a 5'-5'-linked, imidazolium-bridged dinucleotide intermediate, which is a highly reactive substrate formed by two activated monoribonucleotides. We are utilizing X-ray and neutron crystallography to mechanistically study the RNA enzyme-free polymerization and ligation, which are catalyzed by 2-aminoimidazolium-bridge or ribozymes. We are also interested in the functions of mirror-image nucleic acids in molecular evolution, to explore the possible rationale of the biomolecular homochirality in Origins of Life.
Synthetic RNA nanostructures for targeted drug delivery to treat cancers
The rapid development of nucleic acid nanotechnology provides a novel perspective for drug delivery, tissue engineering, biosensing and much more. Our lab try to utilize RNA nanotechnology to develop a platform as the efficient and precise drug delivery tool with higher stability and lower toxicity in vivo. Several short RNA fragments can be designed, programmed and manipulated to assemble into the well-defined 3D objects with precise architecture in the nanometer range, and, in principle, any functional moieties can be included as part of the nanostructure, including DNA, RNA, protein or small molecules. The synthetic mirror-image synthetic RNA can be applied to construct the L-type nanostructure and the intrinsic stability of L-type conformation will offer the delivery tool with dramatic enhanced stability. The current interests include using L-RNA three-way-junction nanoparticles to treat Human Triple-Negative Breast Cancer, Prostate Cancer and Multiple Myeloma cancer.
