Making nucleic acid drugs currently requires toxic solvents and expensive, hard-to-scale chemical processes. This project aims to replace that entire manufacturing chain with enzymes that work in plain water at room temperature. The problem is straightforward. Drugs like mRNA vaccines, antisense oligonucleotides, and short interfering RNAs are made by solid-phase chemical synthesis, which uses hazardous reagents and generates problematic waste. Scaling up production for widespread use is slow and costly. The researchers propose a biological alternative: engineered polymerase or ligase enzymes that add modified nucleotide building blocks one at a time to a starter strand, without needing a template. The growing chain is anchored to a water-compatible solid support or later separated by membranes, allowing easy product isolation. If this works, the impact is on manufacturing infrastructure. Drug companies could produce nucleic acid therapeutics and vaccines faster, at lower cost, and without toxic waste. The process uses nucleotide monomers that are simpler to make and store than current chemical precursors. This could lower barriers to producing essential medicines at industrial scale, particularly for conditions where oligonucleotide therapies are already proven but too expensive to manufacture broadly.
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Nucleic acid-based therapeutics comprise a rapidly expanding category of drugs that have the potential to treat a broad range of genetic and infectious diseases, cancer, cardiovascular disorders etc. Several antisense oligonucleotides (ASOs), short interfering RNAs (siRNAs) and mRNA vaccines have recently been approved and many are under clinical trials. Therapeutic oligonucleotides contain modified ribose moieties and phosphorothioate linkages for improved stability in the cellular environment. Many of the world's top pharmaceutical and biotech companies are now engaged in developing ''safe and effective'' nucleic acid (NA) therapeutics. Currently, modified NAs are produced by solid-phase oligonucleotide synthesis (SPOS) which uses toxic/deleterious reagents and solvents, making the scale-up problematic and expensive. Herein, we propose to establish a novel sustainable bio-based route towards modified nucleic acids, which will involve iterative oligo synthesis in water under mild conditions, utilising benign enzymes and renewable precursors. Modified nucleotide monomers will be synthesised and added to an initiator oligo using template-free, engineered polymerase or ligase enzymes with sequential coupling followed by 3'-deblocking steps. Initially, PEG-based watercompatible solid supports will be used to immobilize the initiator oligo to enable easy isolation of the product. This can be later replaced by emerging membrane separation technology enabling oligo assembly at higher concentrations. Our approach uses nucleotide triphosphate or monophosphate monomers that are easier to prepare, store, and handle, compared with the current monomers used in SPS. We envisage that our proposed methodology would enable widespread production of nucleic acids therapeutics and vaccines, facilitating faster, low-cost, and non-toxic manufacturing of essential medicines at an industrial scale.
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