title: Beyond cyclosporine A: conformation-dependent passive membrane permeabilities of cyclic peptide natural products.
abstract: Many cyclic peptide natural products are larger and structurally more complex than conventional small molecule drugs. Although some molecules in this class are known to possess favorable pharmacokinetic properties, there have been few reports on the membrane permeabilities of cyclic peptide natural products. Here, we present the passive membrane permeabilities of 39 cyclic peptide natural products, and interpret the results using a computational permeability prediction algorithm based on their known or calculated 3D conformations. We found that the permeabilities of these compounds, measured in a parallel artificial membrane permeability assay, spanned a wide range and demonstrated the important influence of conformation on membrane permeability. These results will aid in the development of these compounds as a viable drug paradigm.
authors.affiliation: Department of Chemistry & Biochemistry, University of California, Santa Cruz, CA 95064, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Ahlbach
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
authors.forename: Katrina W
authors.initials: KW
authors.lastname: Lexa
authors.affiliation: Department of Chemistry & Biochemistry, University of California, Santa Cruz, CA 95064, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Bockus
authors.affiliation: Department of Chemistry & Biochemistry, University of California, Santa Cruz, CA 95064, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Chen
authors.affiliation: Department of Chemistry & Biochemistry, University of California, Santa Cruz, CA 95064, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Crews
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.affiliation: Department of Chemistry & Biochemistry, University of California, Santa Cruz, CA 95064, USA.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Lokey
mesh_terms: D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D016572:Cyclosporine / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008567:Membranes, Artificial; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001688:Biological Products; D008567:Membranes, Artificial; D010456:Peptides, Cyclic; D016572:Cyclosporine
keywords: PAMPA; cyclic peptide; cyclosporine; permeability