Trehalose is an autophagy-promoting disaccharide,which can improve and delay chronic diseases like neurodegenerative diseases and atherosclerosis,but its bioavailability is severely restricted by endogenous trehalase ...Trehalose is an autophagy-promoting disaccharide,which can improve and delay chronic diseases like neurodegenerative diseases and atherosclerosis,but its bioavailability is severely restricted by endogenous trehalase in mammals.Trehalase inhibitor is a promising and effective way to enhance trehalose bioavailability by preventing trehalose from hydrolyzing.However,previously reported trehalase inhibitors still face safety of long-term use and promiscuous inhibition on intestinal glycosidases.This study carried out a high-throughput virtual screening through molecular pool-based molecular docking combined with in vitro inhibition experiments to screen trehalase inhibitors naturally derived from foods.Out of 1769 small molecules,which include 115 analogs of trehalose,natural monosaccharides,disaccharides,trisaccharides,imidazoles and their derivatives,as well as 20 natural amino acids and their 400 dipeptides,isomaltose,α-isomaltulose,and isomaltitol exhibited the best inhibitory activities,beyond as traditional sweetener and prebiotic.Best of all,isomaltose showed the half maximal inhibitory concentration(IC50)and inhibition constant(Ki)values on trehalase of 5.59 and(2.1760±0.3431)mmol/L,respectively.Moreover,isomaltose was resistant to the simulated digestive environment and did not affect intestinal glycosidases such asα-glucosidase and glucoamylase,making it a reliable edible candidate for a trehalase inhibitor.This study provides new insights into the virtual screening-based identification of new food-derived trehalase inhibitors for enhanced integrity and bioavailability of orally administered trehalose,especially repurposing a prebiotic for another new use as trehalase inhibitor.展开更多
基金supported by the National Natural Science Foundation of China(32360564)the Guangxi Science and Technology Major Project(2021AA17011)the Nanning Government Specially-invited Expert Program,and Guangxi University Natural Science and Technological Innovation Development Multiplication Plan Project(2022BZRC010).
文摘Trehalose is an autophagy-promoting disaccharide,which can improve and delay chronic diseases like neurodegenerative diseases and atherosclerosis,but its bioavailability is severely restricted by endogenous trehalase in mammals.Trehalase inhibitor is a promising and effective way to enhance trehalose bioavailability by preventing trehalose from hydrolyzing.However,previously reported trehalase inhibitors still face safety of long-term use and promiscuous inhibition on intestinal glycosidases.This study carried out a high-throughput virtual screening through molecular pool-based molecular docking combined with in vitro inhibition experiments to screen trehalase inhibitors naturally derived from foods.Out of 1769 small molecules,which include 115 analogs of trehalose,natural monosaccharides,disaccharides,trisaccharides,imidazoles and their derivatives,as well as 20 natural amino acids and their 400 dipeptides,isomaltose,α-isomaltulose,and isomaltitol exhibited the best inhibitory activities,beyond as traditional sweetener and prebiotic.Best of all,isomaltose showed the half maximal inhibitory concentration(IC50)and inhibition constant(Ki)values on trehalase of 5.59 and(2.1760±0.3431)mmol/L,respectively.Moreover,isomaltose was resistant to the simulated digestive environment and did not affect intestinal glycosidases such asα-glucosidase and glucoamylase,making it a reliable edible candidate for a trehalase inhibitor.This study provides new insights into the virtual screening-based identification of new food-derived trehalase inhibitors for enhanced integrity and bioavailability of orally administered trehalose,especially repurposing a prebiotic for another new use as trehalase inhibitor.
