Strong inhibition of cholera toxin by multivalent GM1 derivatives

ORGN 683

Roland J. Pieters, r.j.pieters@uu.nl1, Aliaksei V. Pukin2, Hilbert M. Branderhorst1, Carel A. G. M. Weijers2, Michel Gilbert3, Rob M. J. Liskamp, r.m.j.liskamp@uu.nl1, Gerben M. Visser, Gerben.Visser@wur.nl2, and Han Zuilhof4. (1) Department of Medicinal Chemistry and Chemical Biology, Utrecht University, P.O.Box 80082, 3508 TB Utrecht, Netherlands, (2) Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703HB Wageningen, Netherlands, (3) Institute for Biological Sciences, National Research Council of Canada, Ontario, K1A OR6, Canada, (4) Laboratory of Organic Chemistry, Wageningen University & Research, Dreijenplein 8, 6703 HB Wageningen, Netherlands

Glycodendrimers were prepared that are composed of multiple arms linked by ‘click' chemistry to the GM1-oligosaccharided (GM1os).  The pentasaccharide GM1os is the natural pentasaccharide to which the cholera toxin binds.  Strong ligands for the toxin have therapeutic potential but can also become part of a detection system of the toxin.  Multivalency is beneficial to increase affinities by simultaneous binding of multiple ligands on different dendrimer arms to different binding sites.  The cholera toxin is highly suited for this approach considering its high (penta) valency.  The prepared compounds bound to the toxin with very high potencies.  The tetravalent GM1os derivative bound over 80,000-fold more strongly than a monovalent GM1os-containing reference compound.  The potency was due to 1) the availability of the natural GM1os ligand in relatively large quantities, 2) a multivalent display of sufficient valency and spacer length.