| The diarrheal diseases caused by cholera toxin (CT) and E. coli heat-labile enterotoxin (LT) continue to contribute in large part to the total number of infectious disease-related deaths world-wide each year. Currently, no prophylaxis is available for these toxins; and the efficacy of existing vaccines against V. cholerae is short-lived. We are currently engaged in a program aimed at developing synthetic multivalent ligands with ultra-high affinity for the symmetric B pentamer of these toxins in an effort to block ganglioside receptor binding, a critical step in the function of these toxins. We report here the design, synthesis, and evaluation of monovalent, bivalent, pentavalent, and decavalent ligands targeting the B pentamer of CT and LT. The most potent multivalent compounds represent an improvement in affinity of a factor of 12.5 million over the constituent monovalent ligand. These “macroligand” compounds may serve as novel leads in the development of therapeutic agents for the treatment and/or prevention of CT or LT-induced diarrheal disease. |
