Specific protein-carbohydrate
recognition plays an important role in a huge variety of biological processes.
Examples range from viral infections through immune reactions to aberrant
decoration of cell walls with glycan chains in cancer. The ability to interfere
with and control such processes in order to combat or prevent disease requires
a profound understanding of the basis of specific protein-carbohydrate
interactions. Although crystallography has delivered valuable structural data
on protein-carbohydrate complexes, attempts to use such data for the rational
design of inhibitors with therapeutic potential had limited success. One reason
for this is that protein-carbohydrate interactions are rather weak, despite
their exquisite specificity. On the other hand, NMR offers a number of
techniques that are ideally suited to explore weak ligand-protein interactions.
Here, it will be explained how such experiments can be beneficial in the search
for compounds that inhibit protein-carbohydrate interactions. A human blood
group glycosyltransferase and a norovirus capsid will serve as examples where
NMR studies led to the discovery of promising inhibitor prototypes.
References:
[1] Jorgensen, R., Grimm, L.L.,
Sindhuwinata, N., Peters, T. and Palcic, M.M. (2012) A glycosyltransferase
inhibitor from a molecular fragment library simultaneously interferes with
metal ion and substrate binding. Angew Chem Int Ed Engl, 51,
4171-4175.
[2] Fiege, B., Rademacher, C.,
Cartmell, J., Kitov, P.I., Parra, F. and Peters, T. (2012) Molecular Details of
the Recognition of Blood Group Antigens by a Human Norovirus as Determined by
STD NMR Spectroscopy. Angew Chem Int Ed Engl, 51, 928-932.
[3] Rademacher, C., Guiard, J.,
Kitov, P.I., Fiege, B., Dalton, K.P., Parra, F., Bundle, D.R. and Peters, T.
(2011) Targeting norovirus infection-multivalent entry inhibitor design based
on NMR experiments. Chemistry, 17, 7442-7453.
