Enzyme Kits to Facilitate the Integration of Biocatalysis into Organic Chemistry – First Aid for Synthetic Chemists

Fessner, Nico D.; Badenhorst, Christoffel P. S.; Bornscheuer, Uwe T.

doi:10.1002/cctc.202200156

Cited by 11 publications

(7 citation statements)

References 164 publications

(363 reference statements)

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“…98 As a result of significant efforts in late-stage development, the number of off-the-shelf, commercially available enzymes for early process development continues to expand, providing more options for rapid synthetic enablement. 99 Furthermore, improvements being made in accelerating enzyme evolution have the potential to expand the reach and impact of biocatalysis in the early development space where timelines are increasingly tight.…”

Section: ■ Future Outlookmentioning

confidence: 99%

The Evolving Nature of Biocatalysis in Pharmaceutical Research and Development

France

Lewis

Martínez

2023

JACS Au

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Biocatalysis is a highly valued enabling technology for pharmaceutical research and development as it can unlock synthetic routes to complex chiral motifs with unparalleled selectivity and efficiency. This perspective aims to review recent advances in the pharmaceutical implementation of biocatalysis across early and late-stage development with a focus on the implementation of processes for preparative-scale syntheses.

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Section: ■ Future Outlookmentioning

confidence: 99%

The Evolving Nature of Biocatalysis in Pharmaceutical Research and Development

France

Lewis

Martínez

2023

JACS Au

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“…On the discovery side, the chemical diversity produced by libraries of engineered enzymes could be used for lead diversification (Fessner et al, 2022). Libraries of enzymes could be incubated with the lead and incubation extracts screened for pharmacological activity in high throughput fashion, to identify both active and inactive metabolites (Fura et al, 2004).…”

Section: Opportunities For Accelerating Drug Discovery By the Use Of ...mentioning

confidence: 99%

“…Fessner et al have advocated using commercial libraries of biocatalysts as "enzymatic first aid kits" for medicinal chemistry (Fessner et al, 2022) to address challenges in synthetic chemistry that are too challenging or time consuming to do by chemocatalysis. Enhanced lead diversification and LSF are straightforward applications to imagine, as long as the 'activation energy' associated with adopting a new technology can be addressed.…”

mentioning

confidence: 99%

“…They point out that chemists are not trained in working with unstable biological molecules but biotechnologists who have the skills to express and use enzymes are not usually educated in the principles of chemical synthesis. There is a clear need for interdisciplinary training or greater diversity in medicinal chemistry teams (Fessner et al, 2022). However, the format in which enzymes are provided will also be key to implementation.…”

mentioning

confidence: 99%

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Opportunities for Accelerating Drug Discovery and Development by Using Engineered Drug-Metabolizing Enzymes

Gillam

Kramlinger

2022

Drug Metab Dispos

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The study of drug metabolism is fundamental to drug discovery and development (DDD) since by mediating the clearance of most drugs, metabolic enzymes influence their bioavailability and duration of action. Biotransformation can also produce pharmacologically active or toxic products, which complicates the evaluation of the therapeutic benefit vs. liability of potential drugs, but also provides opportunities to explore the chemical space around a lead. The structures and relative abundance of metabolites are determined by the substrate and reaction specificity of biotransformation enzymes and their catalytic efficiency.Preclinical drug biotransformation studies are done to quantify in vitro intrinsic clearance to estimate likely in vivo pharmacokinetic parameters, to predict an appropriate dose, and to anticipate interindividual variability in response, including from drug-drug-interactions. Such studies need to be done rapidly and cheaply, but native enzymes, especially in microsomes or hepatocytes, do not always produce the full complement of metabolites seen in extrahepatic tissues or preclinical test species. Furthermore, yields of metabolites are usually limiting.Engineered recombinant enzymes can make DDD more comprehensive and systematic.Additionally, as renewable, sustainable and scalable resources, they can also be used for elegant chemoenzymatic, synthetic approaches to optimize or synthesize candidates as well as metabolites. Here we will explore how these new tools can be used to enhance the speed and efficiency of DDD pipelines, and provide a perspective on what will be possible in the future. The focus will be on cytochrome P450 enzymes to illustrate paradigms that can be extended in due course to other drug-metabolizing enzymes. Significance statementProtein engineering can generate enhanced versions of drug-metabolizing enzymes that are more stable, better suited to industrial conditions and have altered catalytic activities,

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“… 4 In this context, hydrolase enzymes such as lipase and amylase have been widely used by chemists to synthesize clinically important molecules using several organic reactions, such as Michael addition, the Aldol reaction, the Henry reaction, and a range of multicomponent reactions. 5 Nevertheless, numerous challenges are associated with enzymatic reactions, such as high operational costs, low thermal stability of the pure enzyme in the reaction conditions, low solubility, low tolerance in the presence of an organic solvent, and low/no reusability, which hinder large-scale applications. 6 To overcome these shortcomings, the immobilization of the enzyme has gathered interest in recent years.…”

Section: Introductionmentioning

confidence: 99%