21 - SUSTAINABILITY: Biohazard

Enzymes represent the pinnacle of sustainable synthesis. In nature, these biological catalysts carry out reactions under the mildest of conditions, on highly complex substrates, in the presence of thousands of impurities – all while operating with exquisite selectivity.

These features are down to the complicated protein structure of biocatalysts and, amazingly, all of their properties can be transferred to the lab.

Biocatalysts are made from cheap starting materials and do not suffer price fluctuation like transition metal catalysts. They can also be made reuseable and are biodegradable at the end of their lifetime.

On paper, biocatalysts are a silver bullet in the sustainable chemist’s arsenal. Indeed, biocatalysts have already made a big impact in pharma. The most well-known example of a drug made biocatalytically is Merck’s Januvia.

In 2010, the company replaced a rhodium-based amination step in the synthesis of this blockbuster drug with a reaction utilising a highly evolved transaminase enzyme. The biotransformation resulted in a 10-13% increase in yield, 53% increase in productivity and a 19% reduction in solid waste including eliminating all heavy metals from the synthesis.

Late-stage changes to a drug’s synthetic route can require expensive refiling with regulatory authorities. Therefore, synthetic optimisation is desirable before a compound enters clinical trials. For Januvia, the directed evolution of the transaminase enzyme took an entire year and the drug was already on the market by the time the biocatalytic process was live. It is reportedly this time-lag to get biocatalytic methods running that has hindered broader uptake in the pharma industry.

The time required to optimise biocatalytic processes is intimately related to their advantages. For example, the incredible selectivity of biocatalysts means that they tend to have limited substrate scope. Usually, screening is required to find a suitable enzyme for a given reaction. Subsequent protein engineering is then typically required to adapt the enzyme to the required reaction conditions, to improve substrate reactivity, to increase tolerance to organic solvents to solubilize reaction starting materials etc.

Tools like colorimetric screening kits have helped chemists arrive at useful hits very rapidly. Advances in computational techniques to model and visualise protein structures help protein engineers to adapt the binding sites of enzymes to novel reaction substrates.

Early investment in the optimisation of biocatalysts must be balanced against the high attrition rate of drug candidates. So, spending large sums on protein engineering before a clinical read-out can seem unattractive, but leaving optimisation too late can also be costly.

A strategy of finding ‘adequate’ hits by enzymatic screening to provide proof-of-concept, then subsequently optimising the biotransformation at a later stage of the pipeline has helped to de-risk the discovery process for pharma companies.

Right now, we’re just scratching the surface of what biocatalysts can do to improve sustainability in synthesis and pharma. The modern approach of a distributed network of specialist companies along with expanding substrate scope and faster, more reliable optimisation of biocatalysts seems to be heralding the beginning of a golden era for biocatalysts.

That said, even faster optimisation of enzymes and opening the available substrate scope to reactions not even observed in nature represents a major challenge to cement the future success of the biocatalysis industry.