The Promise of Macrocycles

The majority of therapeutics are either small molecule compounds or biologics. Small molecules usually act by binding to discrete hydrophobic pockets on a target protein and can be delivered into cells relatively predictably. However, the majority of therapeutic targets do not have such binding sites and so are not addressable with small molecules. Biologics, being significantly larger molecules, can disrupt biological processes in broader ways, but are largely limited to targets that are accessible from the outside of a cell. Because of this, many therapeutic targets are considered “undruggable” with current approaches. Intracellular protein-protein interactions, which are central to many disease processes, including cancer metastasis, inflammation and fibrosis, are often cited as belonging to a target class that could have profound therapeutic potential if tools were available to modulate it.

Macrocyclic peptides offer the potential to address these currently undruggable targets. They are comprised of cyclic peptides or peptide-like scaffold components, typically 500 to 2,000 molecular weight. Because of their size, macrocycles can interact across a relatively large area of a protein compared to small molecules. Functional side chain groups can be added to the cyclic scaffold, allowing interactions with different regions of the protein. As a result, these compounds are theoretically capable of exquisite specificity. There are a number of approved drugs in the macrocycle class, most derived from natural products. These are exemplified by cyclosporine, an orally bioavailable, passively cell permeable macrocycle that is made up of 11 amino acids (ca. 1200 molecular weight). Cyclosporine falls well outside Lipinski’s Rule of Five that predicts drug-like properties; the molecule’s conformational flexibility is believed to enable it to be cell permeable and orally bioavailable.

There have been significant efforts to develop synthetic macrocyclic peptide drugs, including large scale screening programs using natural-product derived libraries and chemistry-based approaches to constrain conformation of the molecules. Identifying macrocycles that bind with good affinity and specificity has been demonstrated to be achievable for a number of targets. However, realizing the full potential of this drug class has been challenged by difficulties in understanding and predicting pharmacokinetics, cell permeability and oral bioavailability. The conformational complexity of macrocycles has prevented, until now, a systematic approach to the design of permeable compounds in this drug class and thus has greatly limited the ability of drug developers to address important target fields such as intracellular protein-protein interactions. Indeed, the majority of macrocycles now in development are targeted to extracellular targets.