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by Cameron R. Pye, William M. Hewitt, Joshua Schwochert, Terra D. Haddad, Chad E. Townsend, Lyns Etienne, Yongtong Lao, Chris Limberakis, Akihiro Furukawa, Alan M. Mathiowetz, David A. Price, Spiros Liras, and R. Scott Lokey

Macrocyclic peptides are considered large enough to inhibit “undruggable” targets, but the design of passively cell-permeable molecules in this space remains a challenge due to the poorly understood role of molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and molecular weights (∼800 Da < MW < ∼1200 Da). Analysis by the parallel artificial membrane permeability assay revealed a steep drop-off in apparent passive permeability with increasing size in stark disagreement with current permeation models. This observation, corroborated by a set of natural products, helps define criteria for achieving permeability in larger molecular size regimes and suggests an operational cutoff, beyond which passive permeability is constrained by a sharply increasing penalty on membrane permeation…

January 6, 2017
Journal of Medicinal Chemistry
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