The effect of backbone cyclization on PK/PD properties of bioactive peptide-peptoid hybrids: The melanocortin agonist paradigm

Oded Ovadia, Yaniv Linde, Carrie Haskell-Luevano, Marvin L. Dirain, Tanya Sheynis, Raz Jelinek, Chaim Gilon, Amnon Hoffman

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)580-589
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number2
DOIs
StatePublished - Jan 15 2010

Keywords

  • Backbone cyclization
  • Melanocortin
  • Peptomers

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