E. coli Strain Transforms Pyrimidines
Chemical production of pyrimidine nucleosides by a number of primarily Chinese and Indian companies has allowed oligos, incorporating modified uridines and cytosines, to be generated cost-effectively on an industrial scale, Michine points out. Conversely, the production of purine nucleoside analogues by chemical routes has been proven, to date, as time-consuming, complicated, and expensive.
“Our biotransformation technology circumvents the problems of traditional synthetic routes, thanks to a particularly compliant strain of E. coli generated by Metkinen’s scientists, last year,“ Michine says. “This bacterial strain allows us to carry out efficient transformation of pyrimidine nucleoside analogues into corresponding modified purine analogues via enzymatic transglycosilation. In essence, we have generated a bacterial strain that can be taught to accept different donors, enabling the production of about 20 different purine analogues on a laboratory scale.“
Metkinen’s first major customer for its biotransformation technology was Geron (www.geron.com). Through this partnership, Metkinen achieved scale up of purine 3´-amino-2´,3´-dideoxyribonucleosides, required by Geron for its development-stage compound GERN163L, Michine states.
“Importantly, we subsequently succeeded in scaling up production of 2´-deoxy-2´-fluoroadenosine (2´-Fluoro A) and 2´-deoxy-2´-fluoroguanosine (2´-Fluoro G). Previously, the use of these molecules in commercial-scale oligonucleotide synthesis had been prohibitively expensive, but our technology has lowered production costs four- to five-fold. This has opened up a whole new avenue of product development opportunities in nucleotide-based therapeutics and siRNAs, where 2´-Fluoronucleosides are used for stabilization.“
Metkinen Chemistry is now in the process of expanding its genetic engineering unit to further exploit the commercial utility of its biotransformation technology. “By talking to companies we are finding out exactly what the industry needs,“ Michine maintains. “We have been approached by many companies looking for a production route for their molecules, opening up a new market for our expertise. By developing our bacterial strains and process skills further, we expect to enable the cost-effective manufacture of oligo-based therapeutic candidates that would otherwise be too expensive to contemplate commercially.“