Molnupiravir (pictured) is an oral antiviral drug for the treatment of COVID-19. It is a nucleoside analog originally developed to treat influenza. Molnupiravir works against viral infections by interfering with viral RNA replication.

John A. McIntosh, Patrick S. Fier, Merck & Co., Inc., Rahway, NJ, USA, and colleagues have developed a short, high-yielding, and sustainable three-step synthesis of molnupiravir. The team started from ribose and used a biocatalytic cascade to synthesize the target compound.

Ribose was first 5-acylated using isobutyric anhydride and an immobilized lipase enzyme. Then, the resulting 5-isobutyryl ribose was converted to ribosyl-1-phosphate and reacted with uracil using several optimized enzymes, including an engineered ribosyl-1-kinase and uridine phosphorylase. In a final step, an oxime group was introduced at the uracil unit, using hexamethyldisilazane (HMDS), NH₄HSO₄, and imidazole to promote the transformation.

The new synthetic route is much shorter and has a seven-fold higher overall yield than the originally used route. Since it uses only simple raw materials and enzymes, it could provide a rapid supply of molnupiravir on a large scale.

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• Engineered Ribosyl-1-Kinase Enables Concise Synthesis of Molnupiravir, an Antiviral for COVID-19,
  John A. McIntosh, Tamas Benkovics, Steven M. Silverman, Mark A. Huffman, Jongrock Kong, Peter E. Maligres, Tetsuji Itoh, Hao Yang, Deeptak Verma, Weilan Pan, Hsing-I Ho, Jonathan Vroom, Anders M. Knight, Jessica A. Hurtak, Artis Klapars, Anna Fryszkowska, William J. Morris, Neil A. Strotman, Grant S. Murphy, Kevin M. Maloney, Patrick S. Fier,
  ACS Cent. Sci. 2021.
  https://doi.org/10.1021/acscentsci.1c00608

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• Collection: SARS-CoV-2 Virus
  What we know about the new coronavirus and COVID-19