title: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors.forename: Cameron R
authors.identifier: 0000-0002-4122-2078
authors.initials: CR
authors.lastname: Pye
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors.forename: William M
authors.identifier: 0000-0002-2881-7704
authors.initials: WM
authors.lastname: Hewitt
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Schwochert
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors.forename: Terra D
authors.initials: TD
authors.lastname: Haddad
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Townsend
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors.forename: Lyns
authors.initials: L
authors.lastname: Etienne
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors.forename: Yongtong
authors.initials: Y
authors.lastname: Lao
authors.affiliation: World Wide Medicinal Chemistry, Groton Laboratories, Pfizer Inc. , Groton, Connecticut 06340, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Limberakis
authors.affiliation: Modality Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Furukawa
authors.affiliation: World Wide Medicinal Chemistry, Cambridge Laboratories, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Mathiowetz
authors.affiliation: World Wide Medicinal Chemistry, Cambridge Laboratories, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: World Wide Medicinal Chemistry, Cambridge Laboratories, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors.forename: R Scott
authors.identifier: 0000-0001-9891-1248
authors.initials: RS
authors.lastname: Lokey
mesh_terms: D000327:Adsorption; D002463:Cell Membrane Permeability / Q000187:drug effects*; D006801:Humans