Design of Tripeptides as a Competitive Inhibitor for HMG-CoA Reductase

This study presents a simple approach in design of tripeptides as a competitive inhibitor for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). HMGR is a major rate limiting enzyme in cholesterol biosynthesis and therefore constitutes the target enzyme of an extensive research to discover new compounds focused on its inhibition. 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 5 tripeptides were designed and synthesized. Among the designed tripeptides, YIE 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 0.23 +/- 0.03 mu M. This is an overall 700-fold increase in inhibitory activity compared to the first isolated LPYP peptide from soybeans. The obtained correlation between the observed and predicted inhibitory activities is good enough in spite of the fact that a different length of peptides was used in the presented design. Statistical analysis suggests that the proposed approach is acceptable in the design of tripeptides.