Effect of structural and conformation modifications, including backbone cyclization, of hydrophilic hexapeptides on their intestinal permeability and enzymatic stability

Shmuel Hess, Oded Ovadia, Deborah E. Shalev, Hanoch Senderovich, Bashir Qadri, Tamar Yehezkel, Yoseph Salitra, Tania Sheynis, Raz Jelinek, Chaim Gilon, Amnon Hoffman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

A library of 18 hexapeptide analogs was synthesized, including sub-libraries of N- or C-methylation of the parent hexapeptide Phe-Gly-Gly-Gly-Gly-Phe, as well as backbone cyclized analogs of each linear analog with various ring sizes. N- or C-methylation as well as cyclization (but not backbone cyclization) have been suggested to improve intestinal permeability and metabolic stability of peptides in general. Here we aimed to assess their applicability to hydrophilic peptides. The intestinal permeability (P app) of the 18-peptide library was in the range of 0.2-6.8 × 10-6 cm/sec. Based on several tests, we concluded that the absorption mechanism of all tested analogs is paracellular, regardless of the structural or conformational modifications. In all cases, backbone cyclization increased Papp (5-fold) in comparison to the linear analogs due to the smaller 3D size and also dramatically decreased peptide proteolysis by brush border enzymes. N- or C-methylation did not enhance the permeability of the linear analogs in this series.

Original languageAmerican English
Pages (from-to)6201-6211
Number of pages11
JournalJournal of Medicinal Chemistry
Volume50
Issue number24
DOIs
StatePublished - 29 Nov 2007

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