Trans-sialidases inhibitor

S. Buchini, A. Buschiazzo, and S. G. Withers, A new generation of specific Trypanosoma cruzi trans-sialidase inhibitors, Angew. Chem. Ini. Ed., 47 (2008) 2700-2703. 

G. B. Kok, M. Campbell, B. Mackey, and M. von Itzstein, Synthesis and biological evaluation of sulfur isosteres of the potent influenza vims sialidase inhibitors 4-amino-4-deoxy- and 4-deoxy-4-guanidino-Neu5Ac2en, J. Chem. Soc. Perkin Trans., 1 (1996) 2811-2815. 

M. F. Amaya, A. Buschiazzo, T. Nguyen, and P. M. Alzari, The high resolution structures of free and inhibitor-bound Trypanosoma rangeli sialidase and its comparison with T. cruzi trans-sialidase,... 

M. Engstler, R. Schauer, M. A. Ferrero-Garcia, A. J. Parodi, T. Storz-Eckerlin, A. Vasella, C. Witzig, and X. Zhu, N-(4-Nitrophenyl)oxamic Acid and Related N-Acylanilines Are Non-competitive Inhibitors of vibrio cholerae sialidase but do not inhibit trypanosoma cruzi or trypanosoma brucei trans-sialidases, Helv. Chim. Acta., 77 (1994) 1166-1174. 

R. Agusti, G. Paris, L. Ratier, A. C. C. Frasch, and R. M. de Lederkremer, Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo, Glycobiology, 14 (2004) 659-670. 

Lactose Derivatives Are Inhibitors of Trans-Sialidase Present in the Mucins... 

NeuSAc is a weak inhibitor of classical sialidases but does not act at all on the trans-sialidases. Correspondingly, the 2,3-difluoro derivative of NeuSAc, forming a covalent intermediate with sialidases and trans-sialidases (see later) was required at high concentrations (20 mM) to inactivate the enzyme completely Since trans-sialidases possess a lactose-binding site in their active center (as described next), lactose and its derivatives, especially lactitol, inhibit the sialic acid transfer of the enzyme from T. cruzi. Oligosaccharides from the mucins of this trypanosome can also inhibit the transfer of sialic acid to, for example, the substrate A-acetyllactosa-mine. It should be noted that heavy metal ions, especially merciuy, are potent inhibitors of sialidases and trans-sialidases. The latter enzymes do not require calcium ions, in contrast to some siaUdases. " " " ... 

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. 

Keywords Chemoenzymatic synthesis Donor- and acceptor-based inhibitors Preparative use Trans-sialidase... 

Fig. 8. Alternative catalytic nucleophiles, (a) Tyrosine functions as the catalytic nucleophile in Clan GH-E sialidases and trans-silalidases, with the assistance of a proximal carboxylate amino acid side chain, (b) Anchimeric assistance in hexosaminidases involving reaction of the A -acetyl group of the substrate with the anomeric carbon to form an oxazoline intermediate in the enzyme active site, (c) Sugar thiazolines are noncleavable S-linked inhibitors of hexosaminidases that use an oxazoline intermediate. Enz5mie selectivity can be further tuned by varying i . ...

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