Isomerase has curated a diverse microbial natural product library from projects over the last 20 years. We store all compound details within our database, including chemical structures and known activity. The team established the database in 2003 and has continued to expand it since.
Whilst serving our partners is the core focus of Isomerase, since the database's inception, our scientists have built up a collection of many molecules, strains, and processes. In most cases, these consist of novel, often engineered, microbial strains capable of producing new or existing compounds. Many of these molecules serve as starting points for small molecule drug development.
In addition to our vast library, we're able to carry out semi-synthetic chemistry to generate diverse molecules. This supplements our bioengineering capabilities and ensures small molecule drug discovery campaigns are well supported.
How can you access our natural product library?
Isomerase builds partnerships underpinned by our technical know-how with many organisations. Formation of license agreements and contractual partnerships provides access to our large library of compounds, with a proven but diverse chemical space.
Example compounds from our natural product database
The following compounds and classes from our natural product library are available for licensing, screening, and partnering.
mTOR inhibitors
Rapamycin and rapalogs (rapamycin analogues) are potent mTOR inhibitors with approved treatments for organ rejection, restenosis, and some cancers. New applications are still appearing with ongoing trials in other therapeutic areas, including several age-related diseases.
- At Isomerase, we have over 20 years of experience with the rapamycin biosynthetic gene cluster, including multiple examples for the discovery and development of therapeutic rapalogs.
- Significantly, Isomerase possesses a plethora of relevant materials and expertise from collaborations with Wyeth, Pfizer, Biotica, and the University of Cambridge.
FKPB inhibitors
FKBPs are a family of peptidyl-prolyl isomerases, present in many tissues. Their inhibition has been shown to have potential both in neuroprotection and neurodegeneration[1].
- We generate non-immunosuppressive, potent FKBP inhibitors based on FK506 (tacrolimus), rapamycin, and FK520 (ascomycin) scaffolds.
- Our molecules have improved properties for the treatment of neurodegenerative diseases and serve as a platform for new FKBP inhibitor discovery.
- Furthermore, we synthesise our FKBP therapeutics in-house by proprietary recombineering technology, thereby allowing us to tailor the structure to project needs.
MIP inhibitors
Inhibition of virulence factors has long been suggested as a non-destructive antimicrobial strategy, therefore minimising resistance proliferation. While most virulence factors are specific to one bacterial genus, limiting applicability, this could open new, long-term methods of treating specific and problematic bacterial infections.
Macrophage infectivity potentiators (MIPs) are peptidyl-prolyl isomerases conserved across a wide range of key human Gram-negative pathogens, including Klebsiella, Acetinobacter, Legionella, Pseudomonas, Burkholderia, Coxiella, and Neisseria. Many of these pathogens belong to the ESKAPE group, where resistance in hospital-acquired infections is a serious concern. Inhibition or knockout of these enzymes leads to a large reduction in virulence[2].
- Isomerase has several bioengineered lead molecules, based on the rapamycin structure, but with mTOR inhibition removed, confirmed as natural product inhibitors of MIPs.
- We produce these molecules by direct fermentation and therefore facilitate low-cost and successful commercialisation.
- Collaborations are ongoing with Prof. Barrie Wilkinson at the John Innes Centre to generate further data on MIP-inhibiting molecules.
Macrolide antibiotics
Macrolide antibiotics span a wide range of compounds with cyclic lactone rings and at least one deoxy sugar modification. Their mechanism of action is to inhibit protein synthesis, specifically achieved via binding to the 50S ribosomal subunit. Interestingly, macrolide antibiotics seem to act as peptide bond blockers preferentially between specific amino acid sequence patterns[3].
- Isomerase synthesises a plethora of macrolide antibiotics, e.g., erythromycin, with established and bespoke glycosylation technology.
Natural product ADC payloads
Combining antibody specificity and established small-molecule efficacy, antibody drug conjugates (ADCs) are one of the most exciting therapeutics in modern medicine.
Many ADCs utilize natural product-based payloads, also known as High Potency Active Pharmaceutical Ingredients (HPAPIs). Multiple clinically approved examples already exist, including taxol, maytansinoids, calicheamicin, and pladienolide B.
- Isomerase has a vast collection of ADC payloads and processes for their production.
- This means we’re well equipped to sell small quantities for research use, enabling partners' screening campaigns or library generation.
- We’ve previously worked with pladienolide B, baflilomycins, leptomycins, and rhizoxins and continue to supply our collaborators with a validated and reliable supply.