Enzyme-Catalyzed Kinetic Resolution of Chiral Precursors to Antiviral Prodrugs.

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ID: 100780
2019
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Abstract
Nucleoside analogues are among the most common medications given for the treatment of viral infections and cancers. The therapeutic effectiveness of nucleoside analogues can be dramatically improved by phosphorylation. The ProTide approach was developed using a phosphorylated nucleoside that is masked by esterification with an amino acid and phenol forming a chiral phosphorus center. The biological activity of the ProTides depends, in part, on the stereochemistry at phosphorus, and thus, it is imperative that efficient methods be developed for the chemical synthesis and isolation of diastereomerically pure ProTides. Chiral ProTides are often synthesized by direct displacement of a labile phenol (-nitrophenol or pentafluorophenol) from a chiral phosphoramidate precursor with the appropriate nucleoside analogue. The ability to produce these chiral products is dictated by the synthesis of the chiral phosphoramidate precursors. The enzyme phosphotriesterase (PTE) from is well-known for its high stereoselectivity and broad substrate profile. Screening PTE variants from enzyme evolution libraries enabled the identification of variants of PTE that can stereoselectively hydrolyze the chiral phosphoramidate precursors. The variant G60A-PTE exhibits a 165-fold preference for hydrolysis of the isomer, while the variant In1W-PTE has a 1400-fold preference for hydrolysis of the isomer. Using these mutants of PTE, the and isomers were isolated on a preparative scale with no detectable contamination of the opposite isomer. Combining the simplicity of the enzymatic resolution of the precursor with the latest synthetic strategy will facilitate the production of diastereometrically pure nucleotide phosphoramidate prodrugs.
Reference Key
xiang2019enzymecatalyzedbiochemistry Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Xiang, Dao Feng;Bigley, Andrew N;Desormeaux, Emily;Narindoshvili, Tamari;Raushel, Frank M;
Journal Biochemistry
Year 2019
DOI
10.1021/acs.biochem.9b00530
URL
Keywords Keywords not found

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