Accessing chemical space around a complex natural product can be difficult. However, we are adept at using biological and chemical techniques to generate natural product analog and variants, including a number of patented and proprietary technologies.
Natural product biosynthesis pathways can be modified at the genetic level using strain engineering and synthetic biology techniques to generate analog produced by direct fermentation. These potential chemical alterations include many that would otherwise be unfeasible to do via semisynthetic chemistry. We can generate targeted libraries around a selected natural product. Compounds can be designed, generated, purified and analysed in-house and supplied to the client or third-party testing facility in a format of your choosing.
Example analog generation methods
Example techniques include:
- Mutasynthesis - allows for the rapid generation of different related structures through the incorporation of synthetic substrates added to the fermentation broth, thereby generating an analog by a direct fermentation route.
- Enzyme engineering - as an example, each of the modular activities in a biosynthetic gene cluster can be altered to facilitate the selection of a specific monomer or oxidative processing.
- Pathway engineering – Starting with a genome sequence and identification of a biosynthetic gene cluster, genes can be engineered to facilitate modifications to the core structure. In addition, late-stage functionalisation of natural products can be performed, e.g. altering or removing glycosylation, methylation, oxidation, reduction or cyclisation.
- Semisynthetic chemistry - we are experienced with small quantities of a precious natural product and carrying out, or managing semisynthetic chemistry campaigns to generate natural product analogs.
- Biotransformation – We can use the Isomerase biotransformation collection. This is a curated collection of microbial strains selected for the biotransformation of natural products.
- Biocatalysis – Following successful biotransformation and identification of the key enzyme(s) or using a previously developed enzyme, analogues can be generated in a similar way to semisynthetic chemistry, but using a biological catalyst.
Example analog generation projects
Example projects have included:
- Accessing novel patent space - the combination of bioengineering and semisynthesis frequently allows access into novel patent space even in areas with extensive patent coverage.
- Improvement of the therapeutic index - By screening analogues of a known natural product, we have been able to identify hits with both improved activity against a target of a compound and reduced off-target toxicity which ultimately leads to an improvement in the therapeutic index.
- Target swap - We have generated analogues of known natural products and reduced the potency of any unwanted activities, while in parallel enriching the previously off-target activity to generate novel products with activity against a new target with a new mechanism of action.
Contact us for more information about natural product analog generation, biotransformation, and analysis of biosynthetic gene clusters or to request a quote.