期刊
APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
卷 178, 期 2, 页码 312-323出版社
HUMANA PRESS INC
DOI: 10.1007/s12010-015-1873-y
关键词
Human squalene synthase; Hypercholesterolemia; Molecular docking; Peptide inhibitor; Phage display
资金
- National Science Council ROC [NSC97 - 2311-B259-04-MY3, NSC99-2113-M-001-024-MY3]
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 mu M) and may have potential to develop further as future hypocholesterolemia agents.
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