Biocatalytic Oligonucleotide Synthesis Technology

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Therapeutic oligonucleotides are a class of drug that has grown in interest over the last few years with the first drug approved by the FDA in only 2017.  By early 2020 a further 10 oligonucleotide drugs had received FDA regulatory approval with many more in the pipeline. 

Traditional chemical routes for oligonucleotide synthesis using phosphoramidite chemistry have drawbacks relating to product yield and purity. These factors have stimulated considerable interest in biocatalytic approaches to oligonucleotide synthesis to overcome the chemical synthesis limitations and help deliver upon a rapidly expanding pipeline of future therapeutic oligonucleotides. 

Enzymes offer the benefits of sustainability, selectivity and cost reduction in pharmaceutical synthesis. Oligonucleotides (and their building blocks – blockmers) have diverse structural complexity and often incorporate unnatural nucleotide modifications to improve their therapeutic potential.  Enzymatic synthesis therefore requires a sophisticated suite of enzyme technologies to effectively tackle both building block and strand construction, whilst accommodating diverse unnatural modifications. Almac has developed a range of biocatalytic products and services to facilitate the challenges posed in biocatalytic oligonucleotide synthesis.

Building upon the strong biocatalytic technology base already available at Almac we have successfully applied this technology to oligonucleotide synthesis using Almac’s selectAZyme™ panels for production of both single stranded and double stranded products.  The technology can be applied to synthesis of siRNA duplexes and other therapeutic oligonucleotides.

We offer the following

  • Screening of enzyme panels to identify enzymes specific for your oligonucleotides
  • Alternative strategies to allow enzymatic production of single and double stranded RNA oligonucleotides
  • Development of cost effective processes using enzymes where single and double stranded oligonucleotides are assembled from blockmers using RNA ligase enzymes
  • Utilise blockmer self-assembly or templating followed by enzyme mediated ligation 
  • Enzyme engineering of Ligase enzymes to further improve your synthesis
  • Scale up of the ligase reaction to multigram scale

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