Rational design and molecular engineering of peptide aptamers to target human pancreatic trypsin in acute pancreatitis

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• 作者：Weiyi Shao ; Wenxian Zhu ; Yanhua Wang…
• 关键词：human pancreatic trypsin ; molecular engineering ; peptide aptamer ; acute pancreatitis
• 刊名：Biotechnology and Bioprocess Engineering
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：21
• 期：1
• 页码：144-152
• 全文大小：630 KB
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• 作者单位：Weiyi Shao (1)
  Wenxian Zhu (1)
  Yanhua Wang (1)
  Jingwei Lu (1)
  Ge Jin (1)
  Yixin Wang (1)
  Wenli Su (1)
  
  1. Emergency Surgery Department, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200-062, China
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Biotechnology
  
• 出版者：The Korean Society for Biotechnology and Bioengineering
• ISSN：1976-3816

文摘

Human pancreatic trypsin (hPT) is an established target for acute pancreatitis (AP) therapeutics. Here, a bioinformatics protocol of protein docking, peptide refinement, dynamics simulation and affinity analysis was described to perform rational design and molecular engineering of hPT peptide aptamers. Protein docking was employed to model the intermolecular interactions between hPT and its cognate inhibitory protein, the human pancreatic trypsin inhibitor (hTI). A number of peptide fragments were cut out from the interaction sites of docked hPT–hTI complexes, from which a decapeptide fragment 13LNGCTLEYRP22 was found to exhibit potent inhibition against hPT (K _i = 5.3 ± 0.8 μM). We also carried out alanine scanning and virtual mutagenesis to systematically examine the independent contribution of peptide residues to binding affinity, and the harvested knowledge were then used to guide modification and optimization of the decapeptide fragment. Subsequently, inhibition studies of nine promising candidates against recombinant hPT were conducted, from which four samples were successfully identified to have high or moderate potency (K _i < 10 μM). In particular, the peptides LQVCTLEYCN and LQICTLEYCT were found to inhibit hPT activity significantly (K _i = 0.23 ± 0.04 and 0.85 ± 0.18 μM, respectively). Structural analysis of hPT–peptide complex systems unraveled diverse chemical interactions such as hydrogen bonds, salt bridges and hydrophobic forces across the complex interfaces.