title: Exploration of Peptide Inhibitors of Human Squalene Synthase through Molecular Modeling and Phage Display Technique.
abstract: 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.
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, 974, Republic of China. shiuan@mail.ndhu.edu.tw.
authors.forename: David
authors.initials: D
authors.lastname: Shiuan
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, 974, Republic of China.
authors.forename: Hwan-Kang
authors.initials: HK
authors.lastname: Lin
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, 974, Republic of China.
authors.forename: Yue-Hao
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan, 115, Republic of China.
authors.forename: Ding-Kwo
authors.initials: DK
authors.lastname: Chang
authors.affiliation: Development Center for Biotechnology, Taipei, Taiwan, 221, Republic of China.
authors.forename: Kao-Jean
authors.initials: KJ
authors.lastname: Huang
authors.affiliation: Department of Applied Chemistry, National Pingtung University, Pingtung, Taiwan, 900, Republic of China.
authors.forename: Lynn
authors.initials: L
authors.lastname: Farh
mesh_terms: D000595:Amino Acid Sequence; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010455:Peptides; D011994:Recombinant Proteins; D013186:Farnesyl-Diphosphate Farnesyltransferase
keywords: Human squalene synthase; Hypercholesterolemia; Molecular docking; Peptide inhibitor; Phage display