Macrocycles

Macrocycles are ring-shaped molecules that can alter protein interactions.

Macrocycles are designed to bind to large surface areas of a protein. In doing so, they can block its ability to interact with other proteins, and may be used to prevent protein-protein interactions that cause disease. At Genentech, we are working with PeptiDream to create macrocycles that can reach and bind their targets more effectively.

Protein interactions make our bodies function. So it’s no surprise that proteins interacting in the wrong way can spark disease.

However, many of today’s medicines are small molecules. Small molecules require crevices in a protein’s structure into which they can nestle and bind, but many proteins have broad, flat surfaces that make it impossible for a small molecule to latch on efficiently. So, when researchers want to change the interaction between two proteins, whether that’s stabilizing protein complexes or preventing proteins from coming together, they often need to think beyond the small molecule.

That’s why we’re working to advance a structural class of molecules called macrocycles. Macrocycles are ring-like molecules that, due to their structure, can potentially cover more space and interact with protein surfaces not well-suited for small molecules. At the same time, they can maintain desirable characteristics of a small molecule, like the ability to be swallowed in a pill. In fact, naturally occurring macrocycles have already proven effective in a range of diseases, like rheumatoid arthritis and Crohn’s disease.

Of course macrocycles aren’t perfect. “Macrocycles can make good medicines, but they’re notoriously difficult to find and modify because of their structure and size,” says Wayne Fairbrother, Director and Senior Staff Scientist, Early Discovery Biochemistry. “People have spent decades trying to make them work.”

In 2015, we began a discovery collaboration with PeptiDream to identify and optimize macrocycle therapeutics. For example, because of their size, one of the biggest challenges is getting these molecules to go where they are needed, whether that’s into the bloodstream or across a cell membrane. Combining in-house discovery efforts, machine learning approaches, and PeptiDream’s Peptide Discovery Platform System (PDPS) technology, we can more rapidly make and test molecular candidates that effectively reach and bind their intended targets. This could one day enable us to treat diseases that have long evaded traditional small molecules.