Director and Scientific Co-Founder Fog Pharmaceuticals, Massachusetts, United States
Helically constrained peptides are an emerging drug modality that allow the targeting of intracellular protein surfaces that are ordinarily inaccessible to small molecules or biologics. We have developed a unique stapled phage display platform that enables the de novo discovery of helical peptide binders to target proteins, and have used this platform to identify dozens of chemical series for a wide range of undruggable targets. High-resolution crystal structures and biochemical studies reveal a diversity of binding modes and mechanisms, including inhibitors, activators, and multimerizers. To rapidly advance these helical hits to molecules with drug-like properties, we have also developed a multiplexed hit-to-lead platform that combines combinatorial peptide synthesis with mass spectrometry-based screening assays for binding affinity, physico-chemical properties, and direct quantification of cytosolic exposure. This platform enables the synthesis and screening of thousands of peptides per week, and we report a case study where this platform is used to optimize a low-micromolar phage hit to a compound with in vivo pharmacodynamic modulation of an intracellular target in less than six months.
