Trypanosomal Trans-sialidases: Valuable Synthetic Tools and Targets for Medicinal Chemistry

Abstract

In contrast to the general hydrolases, trans-sialidase from Trypanosoma cruzi (TcTS) shows excellent regio- and stereoselectivity as well as high yields in transfer reactions. Discussed are the occurrence of trans-sialidases and studies on the transfer mechanism. In detail, the preparative use by chemoenzymatic syntheses with TcTS are outlined with emphasis on the design of modified donor and acceptor substrates. Another section focuses on attempts to develop inhibitors for TcTS, and these endeavors are based on donor- and acceptor-inspired modifications as well as on some completely different structures.

trans-Sialylation: a strategy used to incorporate sialic acid into oligosaccharides

“… 57 Excellent reviews on the structure and function of TcTS have been published 36,42,57–60 as well as reviews on T. cruzi trans -sialidase (TcTS) as a synthetic tool. 61,62 …”

“…The donors for sialic acid are 3′-sialyllactose (3′SL), or sialyl glycosides like methyl umbelliferyl- N -acetyl-neuraminic acid (MUNANA) and p -nitrophenyl- N -acetylneuraminic acid (Neu5Acα p NP) with lower activities for the transfer reaction than 3′SL but with the advantage that the reactions are not reversible. 61,99 Glycoproteins with an appropriate content of Neu5Acα2-3Galβ units, like fetuin containing 8.7% of sialic acids at the non-reducing ends of its oligosaccharides, 100 or the casein glycomacropeptide (GMP) with 4–7% sialic acid, 101 may be used as donors. Fetuin is a commercially available glycoprotein with a transfer rate to Galβ1-4GlcNAc similar to that of α2-3-sialyllactose.…”

Handbook of Carbohydrate-Modifying Biocatalysts

“…In contrast, N-acyl groups larger than propionyl were not accepted, and the same applied to other 5-nitrogensubstituted derivatives of Neu5Ac as well as for KDN, the 5-hydroxy analog of Neu5Ac (Scheppokat et al, 2010). The recent progress of Trypanosoma cruzi trans-sialidase as synthetic tool and biological target has been reviewed by Meinke and Thiem (2012).…”

Access to Galectin-3 Inhibitors from Chemoenzymatic Synthons

“…6,7,8,9 Interestingly a reverse strategy consisting in using temporary protecting groups on acceptor substrates to divert and control the reactivity of glycosyltransferases has been applied to synthesize complex glycoforms. 10,11 Trans-glycosidases whether natural 12 or mutant glycoside hydrolases obtained by directed evolution 13 or rational design 14 as well as glycosynthases 15 are powerful tools for the synthesis of oligosaccharides or glycoconjugates. For example, the design of a trans--N-acetylglucosaminidase engineered from a GH1 glycoside hydrolase able to hydrolyze galactose and glucose but not N-acetyl-D-glucosamine has been reported.…”