Exploration of Peptide Inhibitors of Human Squalene Synthase through Molecular Modeling and Phage Display Technique

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• 作者：David Shiuan ; Hwan-Kang Lin ; Yue-Hao Chen…
• 关键词：Human squalene synthase ; Hypercholesterolemia ; Molecular docking ; Peptide inhibitor ; Phage display
• 刊名：Applied Biochemistry and Biotechnology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：178
• 期：2
• 页码：312-323
• 全文大小：802 KB
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• 作者单位：David Shiuan (1)
  Hwan-Kang Lin (1)
  Yue-Hao Chen (1)
  Ding-Kwo Chang (2)
  Kao-Jean Huang (3)
  Lynn Farh (4)
  
  1. Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, 974, Republic of China
  2. Institute of Chemistry, Academia Sinica, Taipei, Taiwan, 115, Republic of China
  3. Development Center for Biotechnology, Taipei, Taiwan, 221, Republic of China
  4. Department of Applied Chemistry, National Pingtung University, Pingtung, Taiwan, 900, Republic of China
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Biotechnology
  Biochemistry
  
• 出版者：Humana Press Inc.
• ISSN：1559-0291

文摘

Many studies have demonstrated the role of elevated levels of serum cholesterol in the pathogenesis of atherosclerosis and coronary heart disease. Various drugs targeting the key enzymes involved in the cholesterol biosynthesis pathway have been investigated for the treatment of hypercholesterolemia. Human squalene synthase has been one of the most important targets for therapeutic intervention. In the present study, we used the recombinant human squalene synthase as the lure for screening the peptide inhibitors from phage-displayed random peptide library. The tightly bound phages and their derived peptides were further evaluated based on their potential binding capabilities, molecular modeling characteristics and predicted absorption, distribution, metabolism, excretion, toxicity (ADMET) properties. Several hexa-peptides and tetra-peptides were finally synthesized to assay their inhibitory effects toward the recombinant human squalene synthase. The results demonstrated that the hexa-peptide FTACNW and tetra-peptide VACL can inhibit human squalene synthase effectively (with IC50 values near 100 μM) and may have potential to develop further as future hypocholesterolemia agents. Keywords Human squalene synthase Hypercholesterolemia Molecular docking Peptide inhibitor Phage display