title: Design of a highly potent inhibitory peptide acting as a competitive inhibitor of HMG-CoA reductase.
abstract: This study presents a design of a highly potent and competitive inhibitory peptide for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). HMGR is the major regulatory enzyme of cholesterol biosynthesis and the target enzyme of many investigations aimed at lowering the rate of cholesterol biosynthesis. In previous studies, the two hypocholesterolemic peptides (LPYP and IAVPGEVA) were isolated and identified from soy protein. Based on these peptide sequences, a number of peptides were designed previously by using the correlation between the conformational flexibility and bioactivity. The design method that was applied in previous studies was slightly modified for the purpose of the current research and 12 new peptides were designed and synthesized. Among all peptides, SFGYVAE showed the highest ability to inhibit HMGR. A kinetic analysis revealed that this peptide is a competitive inhibitor of HMG-CoA with an equilibrium constant of inhibitor binding (K (i)) of 12 ± 0.4 nM. This is an overall 14,500-fold increase in inhibitory activity compared to the first isolated LPYP peptide from soybeans. Conformational data support a conformation of the designed peptides close to the bioactive conformation of the previously synthesized active peptides.
authors.affiliation: Department of Organic Synthesis, Institute of the Chemistry of Plant Substances, Building 77, Acad. Kh. Abdullaev Str., 100170 Tashkent, Uzbekistan. pakvaleriy@yahoo.com
authors.forename: Valeriy V
authors.initials: VV
authors.lastname: Pak
authors.forename: Minseon
authors.initials: M
authors.lastname: Koo
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Kwon
authors.forename: Lyubov
authors.initials: L
authors.lastname: Yun
mesh_terms: D000595:Amino Acid Sequence; D000924:Anticholesteremic Agents / Q000138:chemical synthesis*; D001667:Binding, Competitive; D002942:Circular Dichroism; D015195:Drug Design; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis*; D060327:Solid-Phase Synthesis Techniques; D012996:Solutions; D030262:Soybean Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010455:Peptides; D012996:Solutions; D030262:Soybean Proteins; D006903:Hydroxymethylglutaryl CoA Reductases