Linking
ligands together via a spacer is a strategy that can dramatically enhance the
potency of a molecule for a suitable target that contains multiple binding
sites within a reasonable distance. This
is particularly true for lectin targets and their inhibition by multivalent
carbohydrates. Bridging binding sites with a well-designed
multivalent system is an interesting challenge.
Most reported systems are composed of flexible, often PEG-based spacer
arms. The promise of more well-defined
spacers is enhanced potency and also improved selectivity for potential
medicinal use. Our results in the
inhibition of the Pseudomonas aeruginosa lectin
LecA will be discussed. Results were
obtained with a spacer based on phenylene ethynylene units and an alternating glucose-triazole-based
system. The first incarnation of the
latter already showed major improvements [1], but with a second generation
further improvements were made.
Molecular modeling of the system is also shown to provide insights into
their dynamic behavior.
Literature
1.
Pertici, F.; Pieters, R.
J. Chem. Commun. 2012, 48, 4008-4010
