Design of competitive inhibitory peptides for HMG-CoA reductase and modeling structural preference for short linear peptides

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is a rate-controlling enzyme in a biosynthesis of cholesterol. In the previous studies, a number of short linear peptides as competitive inhibitors of this enzyme were designed. Short peptides are known as very flexible molecules and a prediction of the structural preferences is an important step in design of such peptides. The effect of the peptide fragmentation in searching of lead peptide candidates was described in the previous design. By using this approach, the present study demonstrates that a relatively stable segment can be selected and it may be used as a basis in investigation of the functionalities of the side chains of the substituted residues during binding. In this connection, a number of heptapeptides were designed by using a substitution in the N-terminus of the designed peptides. The substituted residues were selected to be those that may participate in π-π interaction between non-aromatic groups, and also as the charged residues in some cases. As a result a more active competitive inhibitor for HMGR was designed. The CFGYVAE peptide was found to be more than 25,000-fold active in comparison with the first isolated peptide from soybeans. The obtained spectral and calculation data support to the predicted preference in structures of the designed peptides.