Aggressively Passive: Achieving Truly Small-Molecule-Like Properties in bRo5 Macrocyclic Peptides
Cameron Pye
Co-Founder, Unnatural Products
Natural products, like cyclosporin a, have demonstrated for decades that cyclic peptides can balance drug-like properties and challenging target engagement; achieving the same in synthetic systems has proved very challenging. Herein we report the use of in silico design and parallel synthesis to achieve passive cell permeability in a MW>1000Da compound series. These compounds potently and selectively reactivate wt-p53 by inhibiting their negative regulators MDM2 & MDM4(X) in cellular and in vivo. This compound series demonstrates that the purely synthetic peptides, well beyond the Lipinski space, can achieve passive cell permeability while engaging high-value intracellular targets in a designed, and repeatable manner.