Challenge: Encycle Therapeutics has developed a novel synthetic platform to design enhanced peptide macrocycles called nacellins. Nacellins molecules approximate the dimensions of beta turns extremely well and, although reminiscent of conventional cyclic peptides, exhibit substantially improved passive membrane permeability, as well as stability in the gut and inside cells. However, further chemical modifications of nacellins are needed to render them orally bioavailable and improve their drug-like properties.

Solution: Building on the successful development of its macrocycle platform funded by CQDM, the team tried to elucidate and understand the chemical properties required by nacellins to make them orally bioavailable. By analysing a library of more than 1,500 nacellins, including 350 novel structures, the team has developed new algorithms to help predict which properties of these small circular peptide-like molecules are responsible for their oral bioavailability and cell permeability. The team also continued to expand its library that now contains more than 3,000 nacellins.

Achievements/Impact: By generating its library containing many cell permeable nacellins, Encycle was able to attract the interest of many pharmaceutical industries, including Merck, Pfizer, GSK, AstraZeneca and Takeda, which all screened the library. Furthermore, this project allowed Encycle to raise $12 M to pursue the characterization of these nacellins and further develop ET3764, an orally bioavailable nacellin, which inhibits alpha-4-beta-7 as a mean to treat inflammatory bowel disease.