New and versatile chemical approaches for the synthesis of mRNA and tRNA

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The central dogma of molecular biology states that "DNA makes RNA makes proteins." We are interested in the possibility of intercepting the second step "RNA makes proteins." Two different RNA molecules, messenger RNA (mRNA) and transfer RNA (tRNA) are required in this step; they combine to convert the four letter code of DNA into the sequence of a protein. In principle this process could be manipulated by chemists who can assemble RNA by automated solid-phase methods. This would make it possible to produce chemically modified RNA and in turn modified proteins with new and improved properties by including unnatural building blocks (amino-acids). However, making the required long modified RNA strands to achieve this is beyond the scope of current chemical methods which are based on solid-phase synthesis. Therefore we will develop a new methodology, solid-phase synthesis of RNA combined with chemical ligation, to join together several chemically synthesised RNA strands in a chain to make mRNA molecules that are large enough to be used as therapeutic molecules and which can also be used to make useful proteins. Our synthetic mRNA (chemRNA) will have many advantages over biologically produced RNA. In particular it can be made on a very large scale, and it is possible to introduce many exotic chemical modifications that are not available to biological systems to enhance its stability and improve its ability to target particular organs in the body. This is an important objective because biochemically-derived, mRNA is starting to show promise in immunotherapy, infectious disease control and cancer therapy. Indeed, some mRNAs have even entered clinical trials. However, their development is limited by the difficulty in modifying them to make them stable in the human body. ChemRNA could also be used in combination with chem-tRNA to make proteins that cannot be made by current biochemical or biological methods. Chemical evolution in a test tube could then be used to produce new proteins with enhanced properties for use in many fields including biotechnology and synthetic biology.