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J Med Chem. 2016 Apr 14;59(7):3079-86. doi: 10.1021/acs.jmedchem.5b01740. Epub 2016 Mar 18.

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

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Peptide Chemistry Laboratory, Institute of Biochemistry and Biophysics, University of Tehran , 16 Azar Street, 14176-14335 Tehran, Iran.
Centre for Microbial Diseases and Immunity Research, University of British Columbia , 2259 Lower Mall Research Station, Vancouver, BC V6T 1Z4, Canada.


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.

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