title: The effect of backbone cyclization on PK/PD properties of bioactive peptide-peptoid hybrids: the melanocortin agonist paradigm.
abstract: A peptide-peptoid hybrid (peptomer) library was designed and synthesized, based on the sequence Phe-d-Phe-Arg-Trp-Gly. This sequence was previously found to specifically activate the melanocortin-4-receptor (MC4R) which participates in regulation of energy homeostasis and appetite. The library of peptomers included a peptoid bond in the Phe and/or d-Phe position and consisted of linear and backbone cyclic analogs, differed in their ring size. While the linear peptides rapidly degraded in serum and in brush border membrane vesicles (BBMV's), the linear peptomers were more stable. Backbone cyclic peptomers were also stable under the same conditions. Backbone cyclization significantly increased the intestinal permeability of two peptomers compared to their linear counterparts, in the Caco-2 model. Pharmacological evaluation revealed that two linear and one backbone cyclic peptomer, were found active towards MC4R at the nanomolar range. Thus, the conformational constrains imposed by these local and global modifications affect both the pharmacokinetic and pharmacodynamic properties of the parent peptide. This study demonstrates the potential of imposing backbone cyclization on bioactive peptomers as a promising approach in developing an orally available peptidomimetic drug leads.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 91120, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Ovadia
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Linde
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Dirain
authors.forename: Tanya
authors.initials: T
authors.lastname: Sheynis
authors.forename: Raz
authors.initials: R
authors.lastname: Jelinek
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D003500:Cyclization; D006801:Humans; D008968:Molecular Conformation; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*
chemical_list: D019151:Peptide Library; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4