Abstract

Advances in enzyme engineering technology over the last 15 years has enabled the development of highly efficient manufacturing routes to many blockbuster and late clinical stage drug active pharmaceutical ingredients (APIs). Several blockbuster drug actives including atorvastatin, amoxicillin, esomeprazole and simvastatin have been manufactured using engineered enzymes. Only very recently, however, has the speed of catalyst development approached the rate needed to match pharmaceutical chemical development. While it has long been known that enzymes are capable of establishing chirality in organic synthesis, rapid development of scalable syntheses has only been possible with the establishment of technologies for engineering activity and stability in standard synthetic organic synthesis conditions.

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Advances in enzyme engineering technology over the last 15 years has enabled the development of highly efficient manufacturing routes to many blockbuster and late clinical stage drug active pharmaceutical ingredients (APIs) (1,2). Only very recently, however, has the speed of catalyst development approached the rate needed to match pharmaceutical chemical development (3). While it has long been known that enzymes are capable of establishing chirality in organic synthesis, rapid development of scalable syntheses has only been possible with the establishment of technologies for engineering activity and stability in standard synthetic organic synthesis conditions. There are very few instances in which wild-type enzymes, i.e. unmodified enzymes from nature, have been successfully employed as catalysts for manufacture of drug intermediates. Hydrolysis of penicillin G to 6-aminopenicillanic acid is the most notable exception (4). Indeed, the 2018 Nobel Prize in Chemistry was awarded in part for Frances Arnold’s pioneering work in the development of techniques for Directed Evolution; coupling mutation with selection methods for the adaptation of enzymes as catalysts for efficient synthe ...