title: Peptide to Peptoid Substitutions Increase Cell Permeability in Cyclic Hexapeptides.
abstract: The effect of peptide-to-peptoid substitutions on the passive membrane permeability of an N-methylated cyclic hexapeptide is examined. In general, substitutions maintained permeability but increased conformational heterogeneity. Diversification with nonproteinogenic side chains increased permeability up to 3-fold. Additionally, the conformational impact of peptoid substitutions within a β-turn are explored. Based on these results, the strategic incorporation of peptoid residues into cyclic peptides can maintain or improve cell permeability, while increasing access to diverse side-chain functionality.
authors.affiliation: †Chemistry and Biochemistry University of California, Santa Cruz, California 95064, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Schwochert
authors.affiliation: †Chemistry and Biochemistry University of California, Santa Cruz, California 95064, United States.
authors.forename: Rushia
authors.initials: R
authors.lastname: Turner
authors.affiliation: †Chemistry and Biochemistry University of California, Santa Cruz, California 95064, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Thang
authors.affiliation: †Chemistry and Biochemistry University of California, Santa Cruz, California 95064, United States.
authors.forename: Ray F
authors.initials: RF
authors.lastname: Berkeley
authors.affiliation: †Chemistry and Biochemistry University of California, Santa Cruz, California 95064, United States.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Ponkey
authors.affiliation: †Chemistry and Biochemistry University of California, Santa Cruz, California 95064, United States.
authors.forename: Kelsie M
authors.initials: KM
authors.lastname: Rodriguez
authors.affiliation: ‡Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States.
authors.forename: Siegfried S F
authors.initials: SS
authors.lastname: Leung
authors.affiliation: ∥World Wide Medicinal Chemistry, Groton Laboratories, Pfizer Inc. Groton, Connecticut 06340, United States.
authors.forename: Bhagyashree
authors.initials: B
authors.lastname: Khunte
authors.affiliation: ∥World Wide Medicinal Chemistry, Groton Laboratories, Pfizer Inc. Groton, Connecticut 06340, United States.
authors.forename: Gilles
authors.initials: G
authors.lastname: Goetz
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: §Pharmacokinetics and Drug Metabolism, Cambridge Laboratories, Pfizer Inc. Cambridge, Massachusetts 02139, United States.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.affiliation: ⊥Pharmacokinetics and Drug Metabolism, Groton Laboratories, Pfizer Inc. Groton, Connecticut 06340, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Eng
authors.affiliation: ∥World Wide Medicinal Chemistry, Groton Laboratories, Pfizer Inc. Groton, Connecticut 06340, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shapiro
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 Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.affiliation: †Chemistry and Biochemistry University of California, Santa Cruz, California 95064, United States.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Lokey
mesh_terms: D000818:Animals; D002460:Cell Line; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D010455:Peptides