Exploring the chemical space surrounding a complex natural product can be challenging. However, at Isomerase, we specialise in using biological and chemical techniques to generate natural product analogues, including a number of patented and proprietary technologies.
What are natural product analogues?
Analogues are compounds that share a chemical backbone but present different functional groups or substructures. Despite sharing a core structure, analogues usually exhibit different characteristics, such as their specificity, reactivity, or stability. Therefore, this makes analogues highly valuable in fields like pharma, agritech, or functional materials.
Some applications of analogues are:
- Accessing novel patent space: The combination of bioengineering and semisynthesis often allows access to novel patent areas, even in fields with extensive patent coverage.
- Improvement of the therapeutic index: Screening analogue candidates facilitates the identification of candidates with improved activity against a target and reduced off-target toxicity.
- Target swap: Generating and screening libraries of analogues is useful for identifying activity against novel targets using different mechanisms of action. Hence, a focused screening can be used to minimise the potency of unwanted activities while enhancing previously off-target activity.
What are the methods for the generation of natural product analogues?
At Isomerase, we adapt our approach to generating natural products and their analogues to meet the requirements of your research project.
Analogue production by biosynthesis:
This approach harnesses the power of the cell metabolism to generate natural products via direct fermentation.
- Strain engineering: we modify the strain metabolism and regulatory pathways to redirect the resources towards the production of natural products and their analogues. This approach allows modifications to the structure of the natural product, or late-stage functionalisation, such as altering or removing glycosylation, methylation, oxidation, reduction, or cyclisation. These potential chemical alterations include many that would otherwise be unfeasible to do via semisynthetic chemistry.
- Biotransformation: We express known or predicted gene clusters responsible for the biosynthesis of a natural product in a heterologous host. Alongside strain engineering, this approach allows for the uncovering of new enzymatic activities and the result of their combination. Our proprietary strain collection contains >1500 biotransformation strains suitable for the production of natural compounds and their analogues.
- Biocatalysis: We use enzymes in vitro to introduce functional groups to a natural product obtained by fermentation. This approach enables more efficient reactions under milder conditions, thereby minimising costs associated with extreme temperatures and hazardous waste.
At Isomerase, we specialise in enzyme engineering. Regarding analogue production, we can alter the activity of the enzymes of biosynthetic gene clusters or biocatalytic enzymes to generate novel activities. For this purpose, we have developed EvoSelect®, a proprietary machine-learning software specifically designed to accelerate enzyme optimisation projects.
Analogue production by organic synthesis:
An alternative strategy is to couple chemical synthesis with molecular biology to rapidly generate analogue structures of a natural product.
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Mutasynthesis: We interrupt the natural metabolic pathway and add synthetic substrates to the fermentation broth. This leads to the incorporation of the synthetic molecule into the natural product structure to generate an analogue.
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Semisynthesis: We use synthetic chemical reactions to introduce different functional groups into a natural product structure. This allows creating a library of analogues from the same natural product using different reaction conditions.
How can Isomerase help you?
At Isomerase, we bring together expertise in chemistry, strain bioengineering, bioinformatics, process innovation and enzymes.
We can tailor our services to your needs, applying different approaches to your project. We will design, generate, purify and analyse in-house your compounds of interest and their analogues and supply them to you or a third-party testing facility in a format of your choosing.