Sialic acidC-glycosides with aromatic residues: Investigating enzyme binding and inhibition of Trypanosoma cruzi trans-sialidase

Abstract

Several α-configured C-sialosides were synthesised by cross metathesis and further synthetic derivatisation to obtain ligands for Trypanosoma cruzi trans-sialidase (TcTS), a key enzyme in Chagas disease. Affinities of these compounds to immobilised TcTS were measured by surface plasmon resonance (SPR). The K_D values thus obtained are in the lower millimolar range and will be discussed. The results show the importance of addressing Tyr₁₁₉ and Trp₃₁₂ side chains of TcTS in target oriented ligand synthesis, since these amino acids constitute the acceptor binding region in the active site of TcTS. The best ligand showed a significant decrease of TcTS activity in a preliminary NMR based inhibition assay.