Design of an in vitro biocatalytic cascade for the manufacture of islatravir-Reference-Cited by-同舟云学术

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

Published:2019-12-06 Issue:6470 Volume:366 Page:1255-1259
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Huffman Mark A.¹^ORCID,Fryszkowska Anna¹^ORCID,Alvizo Oscar²^ORCID,Borra-Garske Margie²^ORCID,Campos Kevin R.¹^ORCID,Canada Keith A.¹,Devine Paul N.¹^ORCID,Duan Da²^ORCID,Forstater Jacob H.¹^ORCID,Grosser Shane T.¹^ORCID,Halsey Holst M.¹^ORCID,Hughes Gregory J.¹^ORCID,Jo Junyong¹^ORCID,Joyce Leo A.¹^ORCID,Kolev Joshua N.¹^ORCID,Liang Jack²,Maloney Kevin M.¹^ORCID,Mann Benjamin F.¹^ORCID,Marshall Nicholas M.¹,McLaughlin Mark¹,Moore Jeffrey C.¹^ORCID,Murphy Grant S.¹^ORCID,Nawrat Christopher C.¹^ORCID,Nazor Jovana²^ORCID,Novick Scott²,Patel Niki R.¹^ORCID,Rodriguez-Granillo Agustina³^ORCID,Robaire Sandra A.¹^ORCID,Sherer Edward C.³^ORCID,Truppo Matthew D.¹^ORCID,Whittaker Aaron M.¹,Verma Deeptak³^ORCID,Xiao Li³,Xu Yingju¹^ORCID,Yang Hao¹^ORCID

Affiliation:

1. Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.

2. Codexis, Inc., 200 Penobscot Drive, Redwood City, CA 94063, USA.

3. Computational and Structural Chemistry, Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ 07033, USA.

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

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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