2022
DOI: 10.1126/science.abn2009
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A chemoenzymatic strategy for site-selective functionalization of native peptides and proteins

Abstract: The emergence of new therapeutic modalities requires complementary tools for their efficient syntheses. Availability of methodologies for site-selective modification of biomolecules remains a long-standing challenge, given the inherent complexity and the presence of repeating residues that bear functional groups with similar reactivity profiles. We describe a bioconjugation strategy for modification of native peptides relying on high site selectivity conveyed by enzymes. We engineered penicillin G acylases to … Show more

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Cited by 35 publications
(26 citation statements)
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“…Moreover, biocatalysis will, in the future, also address far more complex molecules, as exemplified already with the multistep, modular synthesis of insulin bioconjugates. [15] Interestingly, the examples summarized in this Highlight have not been established by metabolic engineering in whole cell systems, which was the preferred method to make complex (natural products) in the past. We assume that a completely new pathway with the need to introduce many enzyme activities into the host, undesired side reactions, and the challenge of identifying impurities during drug molecule syntheses in whole cells led to the establishment of the cascades using isolated enzymes.…”
Section: Highlightsmentioning
confidence: 99%
See 1 more Smart Citation
“…Moreover, biocatalysis will, in the future, also address far more complex molecules, as exemplified already with the multistep, modular synthesis of insulin bioconjugates. [15] Interestingly, the examples summarized in this Highlight have not been established by metabolic engineering in whole cell systems, which was the preferred method to make complex (natural products) in the past. We assume that a completely new pathway with the need to introduce many enzyme activities into the host, undesired side reactions, and the challenge of identifying impurities during drug molecule syntheses in whole cells led to the establishment of the cascades using isolated enzymes.…”
Section: Highlightsmentioning
confidence: 99%
“…With further advances in molecular biology, lab automation, and bioinformatics (with machine learning/artificial intelligence to facilitate protein engineering and AlphaFold for structure prediction as the most recent trends), it seems reasonable to assume that we will see even more enzyme cascades and also with even more consecutive enzymatic steps in the future. Moreover, biocatalysis will, in the future, also address far more complex molecules, as exemplified already with the multistep, modular synthesis of insulin bioconjugates [15] …”
Section: The Best Of Both Worldsmentioning
confidence: 99%
“…Mit weiteren Fortschritten in der Molekularbiologie, der Laborautomatisierung und der Bioinformatik (mit maschinellem Lernen/kĂŒnstlicher Intelligenz zur Erleichterung des Protein‐Engineerings und AlphaFold fĂŒr die Strukturvorhersage als neueste Trends) ist davon auszugehen, dass zukĂŒnftig noch weitere Enzymkaskaden entwickelt werden. DarĂŒber hinaus wird sich die Biokatalyse in Zukunft auch mit weitaus komplexeren MolekĂŒlen befassen, wie bereits die mehrstufige, modulare Synthese von Insulin‐Biokonjugaten zeigt [15] …”
Section: Das Beste Aus Beiden Weltenunclassified
“…DarĂŒber hinaus wird sich die Biokatalyse in Zukunft auch mit weitaus komplexeren MolekĂŒlen befassen, wie bereits die mehrstufige, modulare Synthese von Insulin-Biokonjugaten zeigt. [15] Interessanterweise wurden die hier gezeigten Beispiele nicht durch Metabolic Engineering in Ganzzellsystemen hergestellt, was in der Vergangenheit die bevorzugte Methode zur Herstellung komplexer (natĂŒrlicher) Produkte war.…”
Section: Das Beste Aus Beiden Weltenunclassified
“…Several excellent reviews have been published on industrial biocatalysis covering various aspects of enzymatic transformations for drug development. ,,− As such, this perspective does not aim to be comprehensive but rather highlight the current state-of-the-art of preparative enzymatic synthesis in an industrial setting. Therefore, the use of biocatalysis for small-scale pharmaceutical metabolite synthesis, lead diversification, ,,, bioconjugation, and selective protein modification − will not be focused upon in this article.…”
Section: Introductionmentioning
confidence: 99%