Accessing chemical space around a complex natural product can be difficult. However, at Isomerase we specialise in using biological and chemical techniques to generate natural product analogs. These include a number of patented and proprietary technologies.
What are natural product analogs?
Analogues are compounds that share a chemical structure but differ in their functional groups or substructures. Even with a common core structure, analogs frequently present different characteristics, like their reactivity, bioavailability, or solubility. For this reason, analogs are invaluable in fields like pharma, agritech, or functional materials.
Common uses of natural product analogs are:
-
Identifying New Target Activities: Focusing the screening on minimizing the potency of unwanted activities while enhancing previously off-target activity allows the identification of new targets and mechanisms of action.
-
Enhancing the therapeutic index: Screening analog libraries helps identify candidates with improved target activity and reduced off-target toxicity.
-
Accessing novel patent space: By combining bioengineering and semisynthesis, it is often possible to access novel patent areas, even in areas with extensive existing patents.
What techniques are used for generating natural product analogs?
At Isomerase, we tailor our strategy to generating natural products and their analogs to meet the specific demands of your research project.
Analog production by biosynthesis:
This approach harnesses the power of the cell metabolism to generate natural products using direct fermentation.
-
Strain engineering: we genetically modify the strain metabolism and regulatory pathways to redirect the resources towards the production of natural products and their analogs. This approach allows modifications to the core structure of the natural product, or late-stage functionalization, 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 discovery 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 analogs.
-
Biocatalysis: We use enzymes to catalyse the introduction of different functional groups and modifications to a natural product obtained by fermentation. This approach enables more efficient reactions under milder conditions, thereby minimizing costs associated with extreme temperatures and hazardous waste.
At Isomerase, we specialize in enzyme engineering. Concerning analog production, we can alter the activity of the enzymes of biosynthetic gene clusters or biocatalytic enzymes to generate novel activities, such as selecting specific substrates or oxidative processes. In light of this, we have developed EvoSelect®. This proprietary machine-learning software is specifically designed to accelerate enzyme optimization projects.
Analog production by organic synthesis:
An alternative strategy is to couple chemical synthesis with molecular biology to rapidly generate analog structures of a natural product.
- 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 analog.
- Semisynthesis: We use synthetic chemical reactions to introduce different functional groups into a natural product structure. This allows creating a library of analogs from the same natural product using different reaction conditions.
How can we 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.