Modeling of hydrophobic tetrapeptides as a competitive inhibitor for HMG-CoA reductase

Abstract

This study presents a modeling of hydrophobic tetrapeptides acting in a competitive manner against 3‑hydroxy-3-methylglutaryl coenzyme A reductase. This enzyme catalyzes the reductive deacylation of 3‑hydroxy-3-methylglutaryl coenzyme A to mevalonate, using two molecules of nicotinamide adenine dinucleotide phosphate as cofactors, and this reaction represents the rate-limiting step in cholesterol biosynthesis. Thus, it is a target of many investigations in order to control a cholesterol level because the elevated cholesterol level is known as a risk factor of hypercholesterolemia. In previous studies, the two hypocholesterolemic peptides were isolated from soy glicinin. Based on these sequences, a number of the tri-, tetra-, hexa- and heptapeptides were designed in order to improve their inhibitory activities. The peptide fragmentation was applied as a main tool in design. Using the developed design method, a new recognized motif in the designed tetrapeptides was identified. According to the design parameter, the IIIP peptide possessed the most rigid structure among the new designed tetrapeptides. The circular dichroism study confirmed that the observed predominant conformation of the IIIP peptide was close to the type I of a β-turn. The IIIP peptide was determined as the strongest inhibitor among the new designed tetrapeptides. The kinetic study revealed the competitive HMGR inhibition by the peptide, which acted as a bisubstrate blocking an access of HMG-CoA and NADPH to their binding sites. The correlation coefficient (r2) between the predicted and observed peptide activities of 0.91 suggests wide possibilities of the proposed approach to design new peptides that may differ from the previously designed peptides in the recognized motif, sequences, lengths and structural preferences.