title: Discovering Peptide Inhibitors of Human Squalene Synthase Through Screening the Phage-Displayed Cyclic Peptide c7c Library.
abstract: Many drugs for the treatment of hypercholesterolemia are targeting the enzymes involved in human cholesterol biosynthesis pathway. Squalene synthase, the rate-limiting enzyme located at the downstream of cholesterol synthesis pathway, has become a better candidate to develop next-generation hypocholesterolemia drugs. In the present study, we cloned and expressed the recombinant human squalene synthase (hSQS) as the lure to isolate potential peptide inhibitors from screening the conformation-constrained phage-displayed cyclic peptide c7c library. Their binding capabilities were further estimated by ELISA. Their pharmaceutical potentials were then analyzed through molecular modeling and the ADMET property evaluations. Four ennea-peptides and nine tetra-peptides were finally synthesized to evaluate their inhibitory potentials toward hSQS. The results indicate that the ennea-peptide CLSPHSMFC, tetra-peptides SMFC, CKTE, and WHQW can effectively inhibit hSQS activities (IC50 values equal to 64, 76, 87, and 90 μM, respectively). These peptides may have potentials to develop future cholesterol-lowering therapeutics. The ligand-protein interaction analysis also reveals that the inner hydrophobic pocket could be a more critical site of hSQS.
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: Yue-Hao
authors.initials: YH
authors.lastname: Chen
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.|Development Center for Biotechnology, Taipei, Taiwan, 115, Republic of China.
authors.forename: Kao-Jean
authors.initials: KJ
authors.lastname: Huang
authors.affiliation: Department of Chemistry, National Dong Hwa University, Hualien, Taiwan, 974, Republic of China.
authors.forename: Da-Fu
authors.initials: DF
authors.lastname: Tai
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan, 115, Republic of China.
authors.forename: Ding-Kwo
authors.initials: DK
authors.lastname: Chang
mesh_terms: D001435:Bacteriophages / Q000737:chemistry / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy; D008024:Ligands; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D019151:Peptide Library; D010456:Peptides, Cyclic; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase
keywords: Human squalene synthase; Hypercholesterolemia; Peptide inhibitor; Phage display