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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Published in:Science (American Association for the Advancement of Science) Vol. 366; no. 6470; p. 1255
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: Journal Article
Language:English
Published: United States 06.12.2019
Subjects:
Biocatalysis
Biotechnology - methods
Deoxyadenosines - chemistry
Pharmaceutical Preparations - chemical synthesis
Reverse Transcriptase Inhibitors - chemistry
Stereoisomerism
ISSN:1095-9203, 1095-9203
Online Access:Get more information
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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.
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ISSN:1095-9203
1095-9203
DOI:10.1126/science.aay8484