Engineered Ribosyl-1-Kinase Enables Concise Synthesis of Molnupiravir, an Antiviral for COVID-19

Area of Science:

• Biocatalysis
• Medicinal Chemistry
• Virology

Background:

• Molnupiravir (MK-4482) is an investigational antiviral drug for treating COVID-19.
• Rapid and sustainable synthesis is crucial due to high demand and urgency.

Purpose of the Study:

• To develop a short, sustainable, and high-yielding synthesis for molnupiravir.
• To enable rapid manufacturing and supply of molnupiravir.

Main Methods:

• Development of a novel biocatalytic cascade using engineered ribosyl-1-kinase and uridine phosphorylase.
• Implementation of a pyruvate-oxidase-enabled phosphate recycling strategy.
• Comparison with the initial synthesis route.

Main Results:

• The new biocatalytic synthesis is 70% shorter than the initial route.
• The synthesis achieved approximately a 7-fold increase in yield.
• The process utilizes simple raw materials for efficient production.

Conclusions:

• The novel biocatalytic cascade offers a streamlined and efficient method for molnupiravir synthesis.
• This approach is sustainable and adaptable for large-scale manufacturing.
• The biocatalytic strategy has potential applications in general nucleoside synthesis.