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Engineering a Biocatalyst to Support a Novel Preparation of Blockbuster Statin Drugs
Author(s) -
Belecki Katherine
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.922.15
Subject(s) - pharmacophore , rosuvastatin , atorvastatin , biocatalysis , combinatorial chemistry , chemistry , population , aldolase a , pharmacology , computational biology , computer science , medicine , biochemistry , enzyme , biology , ionic liquid , catalysis , environmental health
Rosuvastatin (Crestor®) and atorvastatin (Lipitor®) belong to a class of cholesterol‐lowering blockbuster drugs known as statins. In the US alone, approximately 25% of the population over 45 years old takes statins, and new prescription guidelines may lead to an increase in that number. Based on these projections, it is likely that statin therapy will continue to remain the standard of treatment for hyperlipidemia and that the market for these cholesterol‐lowering drugs will remain strong. Accordingly, the development of more efficient and “greener” strategies for the preparation of rosuvastatin in particular, and of statins in general, is a timely and relevant goal that has clear economic and environmental advantages. Nature's capability to introduce chirality into small molecules is unmatched, and scientists are beginning to harness the power of biocatalysis for enantioselective synthesis of pharmaceuticals and other important target molecules. All statins share a chiral 3,5‐dihydroxyacid side chain that is essential for their pharmacological activity. Construction of this pharmacophore has historically represented the most challenging and wasteful aspect of statin production. Although recent advances have improved stereoselective access to this chiral pharmacophore, its efficient incorporation into the final active ingredient has remained a challenge in some cases. In this work, an engineered biocatalyst based on a naturally occurring aldolase enzyme will be described. Using a structure‐guided rational mutagenesis approach, the substrate tolerance of a bacterial deoxyribose‐5‐phosphate aldolase (DERA) has been altered in order to generate the chiral statin pharmacophore with an additional unique functional handle. This biocatalytic approach enables the direct and efficient incorporation of the statin side chain, resulting in a novel synthetic route to rosuvastatin and other members of this widely‐prescribed class of drugs. Support or Funding Information This work was supported by a VCU Presidential Research Quest Fund Award.