Design of an in vitro biocatalytic cascade for the manufacture of islatravir

Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic reactions into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste gen...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2019-12, Vol.366 (6470), p.1255-1259
Main Authors: Huffman, Mark A, Fryszkowska, Anna, Alvizo, Oscar, Borra-Garske, Margie, Campos, Kevin R, Canada, Keith A, Devine, Paul N, Duan, Da, Forstater, Jacob H, Grosser, Shane T, Halsey, Holst M, Hughes, Gregory J, Jo, Junyong, Joyce, Leo A, Kolev, Joshua N, Liang, Jack, Maloney, Kevin M, Mann, Benjamin F, Marshall, Nicholas M, McLaughlin, Mark, Moore, Jeffrey C, Murphy, Grant S, Nawrat, Christopher C, Nazor, Jovana, Novick, Scott, Patel, Niki R, Rodriguez-Granillo, Agustina, Robaire, Sandra A, Sherer, Edward C, Truppo, Matthew D, Whittaker, Aaron M, Verma, Deeptak, Xiao, Li, Xu, Yingju, Yang, Hao
Format: Article
Language:English
Subjects:
Biocatalysis
Biotechnology - methods
Cascade chemical reactions
Catalysts
Chemical reactions
Chemical synthesis
Chemistry
Cofactors
Deoxyadenosines - chemistry
Directed evolution
Enzymes
Evolution
HIV
Human immunodeficiency virus
Intermediates
Organic chemistry
Pharmaceutical Preparations - chemical synthesis
Purification
Reverse Transcriptase Inhibitors - chemistry
Selectivity
Stereoisomerism
Substrates
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Summary:Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic reactions into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification of intermediates. They also allow reactions to be linked together to overcome an unfavorable equilibrium or avoid the accumulation of unstable or inhibitory intermediates. We report an in vitro biocatalytic cascade synthesis of the investigational HIV treatment islatravir. Five enzymes were engineered through directed evolution to act on non-natural substrates. These were combined with four auxiliary enzymes to construct islatravir from simple building blocks in a three-step biocatalytic cascade. The overall synthesis requires fewer than half the number of steps of the previously reported routes.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aay8484