Molnupiravir (MK-4482)
is an investigational antiviral agent that
is under development for the treatment of COVID-19. Given the potential
high demand and urgency for this compound, it was critical to develop
a short and sustainable synthesis from simple raw materials that would
minimize the time needed to manufacture and supply molnupiravir. The
route reported here is enabled through the invention of a novel biocatalytic
cascade featuring an engineered ribosyl-1-kinase and uridine phosphorylase.
These engineered enzymes were deployed with a pyruvate-oxidase-enabled
phosphate recycling strategy. Compared to the initial route, this
synthesis of molnupiravir is 70% shorter and approximately 7-fold
higher yielding. Looking forward, the biocatalytic approach to molnupiravir
outlined here is anticipated to have broad applications for streamlining
the synthesis of nucleosides in general.
Epidemiologic and genetic evidence suggests that influenza A viruses evolve more rapidly than other viruses in humans. Although the high mutation rate of the virus is often cited as the cause of the extensive variation, direct measurement of this parameter has not been obtained in vivo. In this study, the rate of mutation in tissue culture for the nonstructural (NS) gene of influenza A virus and for the VP1 gene in poliovirus type 1 was assayed by direct sequence analysis. Each gene was repeatedly sequenced in over 100 viral clones which were descended from a single virion in one plaque generation. A total of 108 NS genes of influenza virus were sequenced, and in the 91,708 nucleotides analyzed, seven point changes were observed. A total of 105 VP1 genes of poliovirus were sequenced, and in the 95,688 nucleotides analyzed, no mutations were observed. We then calculated mutation rates of 1.5 x 10-5 and less than 2.1 x 10-6 mutations per nucleotide per infectious cycle for influenza virus and poliovirus, respectively. We suggest that the higher mutation rate of influenza A virus may promote the rapid evolution of this virus in nature.
As
practitioners of organic chemistry strive to deliver efficient
syntheses of the most complex natural products and drug candidates,
further innovations in synthetic strategies are required to facilitate
their efficient construction. These aspirational breakthroughs often
go hand-in-hand with considerable reductions in cost and environmental
impact. Enzyme-catalyzed reactions have become an impressive and necessary
tool that offers benefits such as increased selectivity and waste
limitation. These benefits are amplified when enzymatic processes
are conducted in a cascade in combination with novel bond-forming
strategies. In this article, we report a highly diastereoselective
synthesis of MK-1454, a potent agonist of the stimulator of interferon
gene (STING) signaling pathway. The synthesis begins with the asymmetric
construction of two fluoride-bearing deoxynucleotides. The routes
were designed for maximum convergency and selectivity, relying on
the same benign electrophilic fluorinating reagent. From these complex
subunits, four enzymes are used to construct the two bridging thiophosphates
in a highly selective, high yielding cascade process. Critical to
the success of this reaction was a thorough understanding of the role
transition metals play in bond formation.
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