A Chemoenzymatic Synthesis of the (RP)-Isomer of the Antiviral Prodrug Remdesivir.
Biochemistry
; 59(33): 3038-3043, 2020 08 25.
Article
in English
| MEDLINE | ID: covidwho-713002
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Adenosine Monophosphate
/
Alanine
Type of study:
Prognostic study
Topics:
Variants
Limits:
Humans
Language:
English
Journal:
Biochemistry
Year:
2020
Document Type:
Article
Affiliation country:
Acs.biochem.0c00591
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