RT Journal Article
SR Electronic
T1 Towards new cholera prophylactics and treatment: Crystal structures of bacterial enterotoxins in complex with GM1 mimics
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 089607
DO 10.1101/089607
A1 Julie E. Heggelund
A1 Alasdair Mackenzie
A1 Tobias Martinsen
A1 Pavel Cheshev
A1 Anna Bernardi
A1 Ute Krengel
YR 2016
UL http://biorxiv.org/content/early/2016/11/25/089607.abstract
AB Cholera is a life-threatening disease in many countries, and new drugs are clearly needed. C-glycosidic antagonists may serve such a purpose. Atomic resolution crystal structures of these compounds in complexes with the cholera toxin give unprecedented atomic details of the molecular interactions, and show how the inhibitors efficiently block the GM1 binding site. These molecules are well suited for development into low-cost prophylactic drugs, due to their relatively easy syntheses and their resistance to glycolytic enzymes. One of the compounds links two toxin B-pentamers in the crystal structure, which may yield improved inhibition through the formation of toxin aggregates. These structures can spark the improved design of GM1 mimics, either alone or as multivalent inhibitors connecting multiple GM1-binding sites. Future developments may further include compounds that link the primary and secondary binding sites. Serving as decoys, receptor mimics may lessen symptoms while avoiding the use of antibiotics.