Open AccessA Chemoenzymatic Synthesis of the (RP)-Isomer of the Antiviral Prodrug Remdesivir
Author(s) -
Andrew N. Bigley,
Tamari Narindoshvili,
Frank M. Raushel
Publication year - 2020
Publication title -
biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.43
H-Index - 253
eISSN - 1520-4995
pISSN - 0006-2960
DOI - 10.1021/acs.biochem.0c00591
Subject(s) - diastereomer , prodrug , chemistry , rna , stereoselectivity , enzyme , stereochemistry , combinatorial chemistry , biochemistry , gene , catalysis
The COVID-19 pandemic threatens to overwhelm healthcare systems around the world. The only current FDA-approved treatment, which directly targets the virus, is the ProTide prodrug remdesivir. In its activated form, remdesivir prevents viral replication by inhibiting the essential RNA-dependent RNA polymerase. Like other ProTide prodrugs, remdesivir contains a chiral phosphorus center. The initial selection of the ( S P )-diastereomer for remdesivir was reportedly due to the difficulty in producing the pure ( R P )-diastereomer of the required precursor. However, the two currently known enzymes responsible for the initial activation step of remdesivir are each stereoselective and show differential tissue distribution. Given the ability of the COVID-19 virus to infect a wide array of tissue types, inclusion of the ( R P )-diastereomer may be of clinical significance. To help overcome the challenge of obtaining the pure ( R P )-diastereomer of remdesivir, we have developed a novel chemoenzymatic strategy that utilizes a stereoselective variant of the phosphotriesterase from Pseudomonas diminuta to enable the facile isolation of the pure ( R P )-diastereomer of the chiral precursor for the chemical synthesis of the ( R P )-diastereomer of remdesivir.