A range of sizes of Gyrocycle^TM macrocyclic peptides can be generated, and a variable number of heterocycle rings incorporated into the product.  The final macrocycle may contain 0-6 heterocycles.

Many different chemical moieties can be accommodated by our technology as shown in Fig. 1.

Other macrocycles have been made incorporating residues with chemical groups suitable for further chemical modification.

Variations around a hit molecule can be made by using different enzymes and reaction schemes, including further tailoring by oxidation of the heterocycles (Thz, Oxz) and decoration with prenyl groups. Using this protocol a single linear peptide substrate will yield a discrete set of modified cyclic peptides (5 in the example shown in Fig. 2), each with a distinct conformation, and a range of target binding and physicochemical properties.

The heterocycles within the backbone of our compounds force the adoption of predictable compact conformations, as shown in Figs. 3 & 4.  These are ideal for matching pharmacophores.

The advantages of Gyrocycle^TM drugs include:

    1. Modulation of challenging targets such as protein-protein interactions
    2. Ability to cross biological membranes and reach intracellular targets
    3. Stability to metabolism
    4. Improved target affinity/specificity
    5. Potential for oral bioavailability
    6. Access to novel patentable chemical space

Benefits of the Technology

•     Unmatched Diversity (unexploited and patentable chemical space)
          -     range of sizes
          -     can use natural/unnatural/synthetic linear substrates
          -     incorporation of heterocycles (reduced and oxidised), 
          -     prenylation and other modifications
•     Cyclisation of sequences not possible using chemical synthesis 
•     Cyclisation of 6  - 12 amino acid linear sequences is possible
•     Cost-effective for early stage testing and hit-to-lead optimisation
•     Easy analogue synthesis
          -     modification of linear substrate peptide
          -     variation of tailoring enzymes
          -     additional chemical tailoring on specific chemical handles
•     Scalability
          -     discovery platform generates diversity in milligram quantities 
          -     individual tailoring enzymes have been produced in bulk
          -     further scale-up underway to produce tailoring enzymes in kilogram quantities
          -     manufacture of all products possible