Tryptic Stability of Synthetic Bactenecin Derivatives Is Determined by the Side Chain Length of Cationic Residues and the Peptide Conformation

Mojtaba Bagheri, Shima Arasteh, Evan F. Haney, Robert Hancock

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Synthetic bactenecins 1 (HHC-10) and 10 (HHC-36), with excellent activities against bacterial superbugs, display low tryptic stability. To investigate factors influencing this stability, a series of 1/10 derived peptides bearing arginine and lysine analogues with varied methylene chains as well as all-d-isomers were synthesized. Whereas incorporation of d-/l-nonproteinogenic amino acids into the turn-forming peptides did not dramatically affect the antimicrobial activities, the degree of peptide cleavage decreased significantly in peptides with the shortest length of cationic side chain and was influenced by the relative conformational stabilities of the turn structure and the stereoselectivity of tryptic digestion. The site of enzymatic cleavage was located at the less conformationally hindered position distant from the turn motif. Isothermal titration calorimetry showed strong and weak constant increments in the generated heat of enzymatic reaction of unstable and slowly degradable peptides with trypsin, respectively, and suggested a one-site binding model for the enthalpy-driven all-d-peptide-trypsin interactions.

Original languageEnglish
Pages (from-to)3079-3086
Number of pages8
JournalJournal of Medicinal Chemistry
Volume59
Issue number7
DOIs
Publication statusPublished - 28 Apr 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this