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. 2020 Aug 25;59(33):3038-3043.
doi: 10.1021/acs.biochem.0c00591. Epub 2020 Aug 10.

A Chemoenzymatic Synthesis of the (RP)-Isomer of the Antiviral Prodrug Remdesivir

Andrew N Bigley  1 , Tamari Narindoshvili  1 , Frank M Raushel  1
Affiliations

A Chemoenzymatic Synthesis of the (RP)-Isomer of the Antiviral Prodrug Remdesivir

Andrew N Bigley et al. Biochemistry. .

Abstract

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 (SP)-diastereomer for remdesivir was reportedly due to the difficulty in producing the pure (RP)-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 (RP)-diastereomer may be of clinical significance. To help overcome the challenge of obtaining the pure (RP)-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 (RP)-diastereomer of the chiral precursor for the chemical synthesis of the (RP)-diastereomer of remdesivir.

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Conflict of interest statement

Notes

Authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Chemical and enzymatic hydrolysis of (SP/RP)-1. Reactions contained 10 mM HEPES-KOH buffer (pH 8.5) and 20% MeOH. The red line represents the time course for the chemical hydrolysis of 34 μM (RP/SP)-1 by 50 mM NaOH. The blue line represents the time course for hydrolysis of a single isomer of (RP/SP)-1 catalyzed by the addition of 29 nM In1W-PTE to 34 μM (RP/SP)-1, followed by hydrolysis of the other isomer by the addition of 50 mM NaOH.
Figure 2.
Figure 2.
31P-NMR spectra of (RP/SP)-1 after hydrolysis catalyzed by In1W-PTE. The remaining substrate was recovered by extraction with DMSO of the reaction solution at various times (a) before the addition of enzyme, (b) 60 min; (c) 105 min; and (d) 190 min incubation.
Figure 3.
Figure 3.
31P NMR spectra of remdesivir in methanol. (a) Spectrum of remdesivir synthesized from pure (RP)-1. ( b) Spectrum of remdesivir synthesized from (RP/SP)-1.
Scheme 1.
Scheme 1.
Biological activation of remdesivir.
Scheme 2.
Scheme 2.
Chemo-enzymatic synthesis of (RP)-remdesivir.
See this image and copyright information in PMC

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