Design of competitive inhibitory peptides for 3-hydroxy-3-Methylglutaryl coenzyme A reductase
Valeriy V Pak1, Shomansur Sh Sagdullaev1, Aleksandr V Pak2
1Laboratory of the Physical and Chemical Methods of Analysis, Institute of the Chemistry of Plant Substances, Building 77, Mirzo Ulugbek Str., 100170, Tashkent, Uzbekistan.
Abstract:
The effectiveness of statins in preventing hypercholesterolemia and associated cardiovascular diseases has been confirmed for a long time. Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). This enzyme plays a key role in the reaction that represents the rate-limiting step in cholesterol biosynthesis. Numerous studies on the properties of food-derived peptides have revealed various bioactivities that influence human health, including the modulation of endogenous cholesterol levels. Ongoing studies have shown that some peptides function using the same mechanism as statins and can be considered another class of compounds for HMGR inhibition.To date, the competitive inhibition of HMGR by peptides has been confirmed for 36 of them. The half-maximal inhibitory concentration (IC50) of the most active food-derived peptide was found to be 12.8 μM, which is significantly lower than statin activity. This review presents approaches for modeling peptides to enhance their activity. Analysis of the peptides' physicochemical characteristics revealed the potential to design a more active peptide by adjusting a single parameter. The most active designed peptide exhibited 700 times the activity of an isolated peptide found in food. These studies demonstrate the potential of using peptides to develop nutraceuticals or drugs that prevent hypercholesterolemia.
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