Macrocycles are compounds with cyclic structures that enable impressive versatility and the unprecedented ability to target a wide range of protein targets. Despite natural discoveries that yielded blockbuster macrocycle drugs, de novo design has been unable to systematically deliver therapeutically successful macrocycles. A key challenge has been achieving the right properties to enable oral dosing and intracellular targeting.

In a near-infinite space of chemical combinations, many macrocycle drug design attempts resembled shots in the dark.

The most famous example of the power of macrocycles is cyclosporine. Isolated from a fungal sample in 1972, its immunosuppressive abilities were identified and eventually it became a drug that dramatically improved the lives of organ transplant patients all over the world. It is orally bioavailable and can enter cells, most importantly T-cells, where it initiates a chain of events that suppress the cytokine IL-2 and dampens a specific immune response that helps transplanted organs remain accepted by the body.

Cyclosporine was lightning in a bottle. It demonstrated how the flexibility of macrocycle structures could deliver incredibly complex mechanisms in an oral format ideal for patient convenience and dose management. As understanding of macrocycle chemistry grew, there was great excitement for a new wave of medicines with the precision of antibodies and the easy oral format of small molecules. In some ways, macrocycles could go beyond these modalities entirely, for example in the breadth of targets amenable to their binding: Some assessments predict as much as 85% of the targetome could be addressed by macrocycles, including the huge range of protein-protein interactions so integral to many diseases.

But cyclosporine’s remarkable structure was the product of evolutionary pressure on many permutations of the molecule over time. Trying to leapfrog that process into direct design yielded decades of frustration as novel macrocycles largely refused to perform their intended mechanism while also being orally bioavailable and cell permeable – the trinity of properties required for true success.

nGen’s parallel synthesis of highly diverse macrocycle compounds using both natural and un-natural amino acids, combined with a broad suite of direct assays, allows us to put selectionary pressure on many generations of macrocycle compounds in record time.

Stand-out advancements include work at Chugai Pharmaceuticals and the laboratories of Lokey lab at UC Santa Cruz and the Baker Lab at the University of Washington. These teams have succeeded in granting high oral availability even to relatively large molecules, which is a central part of our work at Orbis.

The industry has also noted recent data from macrocycle candidates against PSCK9 and IL-23, both highly validated targets in lipid control and inflammation control, respectively, with blockbuster injectables on the market. The new molecules still only present <2% oral bioavailability, even with the aid of permeation enhancers, but they have still been an exciting addition to forward momentum in our field.

This large scale design, synthesis and direct assaying of real compounds brings a systematic big data approach to the field.

It allows us to reliably move towards identifying the structures with the desirable properties we seek: powerful target binding, stability, and membrane permeability (which supports oral bioavailability). Every step is recorded as data to feed into our machine learning capabilities to continually enhance our capabilities.

It took many years for the right technologies to arrive, but we certainly hope the promise of macrocycles for medicine will have made it worth the wait. Follow Orbis on LinkedIn for more updates as we grow our portfolio and team!