X-Genix: Translating Halogenases for Sustainable Synthesis

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1a.i. Brief description of the idea to be taken to proof of concept:The manufacture of over 90% of pharmaceuticals includes a halogenation step, addition of a halogen to a carbon, forming a so-called C-X bond. Analysis of 200 top-selling drugs indicated that > 25% of pharmaceuticals contain this halogen (X-factor) in the final product, including drugs for treatment for conditions such as cancer, diabetes, high cholesterol, stomach ulcers, anaemia, asthma, epilepsy, and others. A further 67% use C-X formation in their manufacture (see Fig. 2).The problem: Whilst the ability to selectively make C-X bonds is essential, current chemical halogenation methods to achieve this are inefficient, expensive and require toxic chemicals. They are often accompanied by poor selectivity, which results in non-selective halogenation and undesired by-products, creating difficulties in the downstream purification process, environmentally detrimental waste and loss of precious material with cost implications (Fig.1). Existing methods for halogenating aromatic substrates generally employ highly reactive reagents, which often generate products in which either only the most nucleophilic position is halogenated or mixtures of products are produced.In addition, generation of halogenating reagents is an energy intensive process; for example, energy used for producing chlorine gas currently required for pharmaceutical manufacture alone accounts for >400,000 metric tons of CO2-emission (equating to CO2-emission of over 87000 cars per annum). Enzymes suitable for industrial halogenation had not been available prior to our patented approach to discovery of novel halogenases with broad substrate scope.Figure 1: Major limitations of current chemical halogenations - toxic reagents, non-selective chemistries, adverse safety and environmental impact.The Opportunity and Breakthrough Innovation Potential: Our X-Genix project provides enzymatic halogenation technology and uses natural tools (bespoke enzymes and salt) to selectively install C-X bonds without waste and whilst reducing costs (Fig. 3). Our USP is the patented approach to finding flavin dependent halogenases (FDHs), a patented toolbox of halogenases and our knowhow in producing, engineering and using these sustainable enzymes for greener, cheaper and safer halogenation processes. Why now? There is a critical push in industry toward displacing chemically catalysed reactions with enzymatic reactions, the ambition being that by 2050, 30% of all industrial reactions should be enzyme driven. Notably, halogenation, one of the most important transformations remains missing from the industrial biocatalysis portfolio. This proposal addresses this deficit.