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

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·2019·Science

Abstract

Maximal efficiency from enzyme cascades: Enzymes are highly selective catalysts that can be useful for specific transformations in organic synthesis. Huffman et al. combined designer enzymes in a multistep cascade reaction (see the Perspective by O'Reilly and Ryan). The approach eliminates purification steps, recycles expensive cofactors, and couples favorable and unfavorable reactions. With the target molecule islatravir, an experimental HIV drug, they optimized five enzymes by directed evolution to be compatible with unnatural substrates and stable in the reaction conditions. Stereochemical purity was amplified at every enzymatic step, and the final synthesis was both atom economical and efficient. Science , this issue p. 1255 ; see also p. 1199

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Authors
Huffman, M. A., Fryszkowska, A., Alvizo, O., Borra-Garske, M., Campos, K. R., Canada, K. A., Devine, P. N., Duan, D., Forstater, J. H., Grosser, S. T., Halsey, H. M., Hughes, G. J., Jo, J., Joyce, L. A., Kolev, J. N., Liang, J., Maloney, K. M., Mann, B. F., Marshall, N. M., McLaughlin, M., Moore, J. C., Murphy, G. S., Nawrat, C. C., Nazor, J., Novick, S., Patel, N. R., Rodriguez-Granillo, A., Robaire, S. A., Sherer, E. C., Truppo, M. D., Whittaker, A. M., Verma, D., Xiao, L., Xu, Y., & Yang, H.
Venue
Science
Published
2019-12-06
Volume
366
Issue
6470
Pages
1255-1259
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2991758999
Cited by
641
References
0
FWCI
20.62
Type
journal article
Language
en
Open access
closed

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

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