Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 12, Pages 3542-3546Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.03.051
Keywords
Fluorinated amino acids; Protease stability; Non-natural amino acids; Peptide design
Funding
- Rosa Luxemburg Stiftung
- Deutsche Forschnungsgemeinschaft (Research Training Group 1582/1 'Fluorine as key element')
- WBI-Wallonie-Bruxelles International
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Several factors reduce the efficacy of natural peptides as drug candidates; chief among these is their rapid digestion by human proteases. Over the last few decades, a number of strategies have been employed to increase the enzymatic stability of peptides, including the introduction of non-natural amino acids. This study aims at the investigation of the effect of side chain fluorination on the stability of peptides in human blood plasma. Ten model peptides with different non-natural amino acids were designed, synthesized and subjected to enzymatic degradation in human blood plasma. The stability of the studied peptides was followed by HPLC analysis and compared to the control peptide built with only proteinogenic residues. Four main hydrolysis products were detected and identified by mass spectrometry, three of them being characteristic cleavage products of the serine protease Elastase. A final enzymatic study with isolated Elastase validated then the outcome of the plasma study. This case study contributes to the application of fluorinated amino acids in the design of proteolytically stable peptides and proteins with potential clinical relevance. (C) 2013 Elsevier Ltd. All rights reserved.
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