Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules.

ABSTRACT: 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.

SUBMITTER: Pye CR 

PROVIDER: S-EPMC5677520 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature