Enzymatic routes to the next generation therapeutics Ania Fryszkowska and Mark Huffman, John McIntosh, Patrick Fier et al. Merck & Co., Inc., USA, Codexis, Inc., USA, Merck & Co., Inc., USA
Biocatalysis has been transforming the pharmaceutical industry. Advances in protein engineering, combined with the explosion of genomic information, mean that we can now identify and improve enzymes for new reactions at unprecedented speed. The benefits of enzyme-catalyzed reactions for sustainable syntheses are well known, but perhaps most powerful is their unique suitability for combination into multi-step sequences. Such cascade reactions can lead to a fundamentally different synthetic design, where the step-count and the number of isolations are significantly reduced. In this talk, we will present how Merck teams of chemists, biologists, and engineers develop biocatalytic manufacturing processes, where complex non-natural molecules such as nucleoside analogs are efficiently constructed in multi-step enzymatic cascades (1-3). Beyond large-scale manufacture, we will discuss the way biocatalytic transformations can accelerate the pace of drug discovery and expand the synthetic chemistry toolbox, enabling the development of greener, sustainable routes of the next-generation therapeutics (3). References 1. Huffman, M. A.; Fryszkowska, A. et al.Science 2019 , 366, 1255–1259. 2. McIntosh, J. A.; Fier, P. S. et al. Engineered Ribosyl-1-Kinase Enables Concise Synthesis of Molnupiravir, an Antiviral for COVID-19. ACS Cent. Sci. 2021 , 7 (12), 1980–1985. 3. McIntosh, J. A. et al. A Kinase-CGAS Cascade to Synthesize a Therapeutic STING Activator" Nature 2022 , accepted.
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