Biocatalytic Production of a Key Chiral Intermediate of the HIV Capsid Inhibitor Lenacapavir

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Abstract
Lenacapavir is a first-in-class viral capsid inhibitor, approved for the treatment of HIV, and which has been shown to give almost complete protection against transmission of the virus. However the high costs currently associated with the manufacture of Lenacapavir place restrictions on its wider application, making the development of cheaper synthetic routes a key priority. Herein we report the development of an engineered aminotransferase for the synthesis of the central chiral amine core of Lenacapavir. Due to the sterically demanding nature of the ketone substrate, a substrate walking approach was adopted during directed evolution to unlock desired aminotransferase activity starting from a parent template with no observable activity for the target reaction. Introduction of ten mutations into an aminotransferase from Ruegeria sp. TM1040 led to the development of a robust engineered aminotransferase that allowed production of the target chiral amine product with high conversions (>98%), isolated yields (>90%) and optical purity (>99% e.e.). This engineered enzyme will facilitate the development of a biocatalytic process to a key chiral intermediate of Lenacapavir in order to reduce its manufacturing costs and thereby enable global access to this important therapy.
Funding Information
  • Bill and Melinda Gates Foundation