Project description
Improved inhibitors against glycosyltransferase enzymes
Many diseases are characterised by a deregulation in the expression or activity of glycosyltransferase enzymes (GTs), which culminates in abnormal glycosylation. Interfering with these enzymes through the development of targeted GT inhibitors has opened new therapeutic avenues for these diseases. However, GT inhibitors must have the capacity to cross the cell membrane in order to have in vivo biological application. To address this, scientists of the EU-funded PyroSuL project are designing new synthetic building blocks that could be used as surrogates for the pyrophosphate moiety in GT inhibitors. Candidates demonstrating high substrate affinity and improved membrane permeability properties will be further exploited for the therapeutic targeting of GTs.
Objective
PyroSuL (Pyrophosphate Surrogates with Low polarity as part of glycosyltransferase ligands) is a project focused on the development of synthetic building blocks acting as surrogates for the pyrophosphate moiety in glycosyltransferase inhibitors. The final aim of this project is obtaining less polar ligands and inhibitors able to permeate across cellular membranes, which is the bottleneck for these inhibitors to have in vivo biological application. Through structure-based design, new surrogates will be explored. Interaction studies will be carried out through firstly computational approaches, and spectroscopic (nuclear magnetic resonance) and spectrometric (mass spectrometry) techniques will be employed. Surrogates showing promising affinity with the pyrophosphate recognition zone will be synthetically incorporated to substrate-like compounds, bearing a nucleoside and a carbohydrate or mimic. Final derivatives are supposed to show good protein affinities and membrane permeability properties.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
NR4 7TJ Norwich
United Kingdom