Abstract
Cholera is a life-threatening disease in many countries, and new drugs are clearly needed. C-glycosidic antagonists may serve such a purpose. Here we report atomic-resolution crystal structures of three such compounds in complexes with the cholera toxin. The structures 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 synthesis 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.
Highlights
The secreted enterotoxins from Vibrio cholerae and enterotoxigenic E. coli (ETEC) cause millions of diarrhoea episodes each year[1, 2]
Inhibitor 1 was crystallized with El Tor (ET) CTB, inhibitor 2 with cCTB and ET CTB, and inhibitor 3 with porcine LTB (pLTB) R13H
Structures presented here were solved to atomic resolution, allowing for detailed analysis of the interactions
Summary
The secreted enterotoxins from Vibrio cholerae and enterotoxigenic E. coli (ETEC) cause millions of diarrhoea episodes each year[1, 2]. At present there are four cholera vaccines on the market; Shanchol (Shantha Biotechnics, India), Euvichol (EuBiologics, Korea), Vaxchora (PaxVax, USA) and Dukoral (Valneva, Sweden), the latter being effective towards www.nature.com/scientificreports/. Both cholera and ETEC-induced diarrhoea[11]. Euvichol and Dukoral are inactivated vaccines that have to be taken in two spaced doses, and are impractical in a situation where rapid protection is required, such as during a cholera outbreak They are most frequently used for travellers from non-endemic areas, and are not effective in children under the age of 1–2 years[12]. By binding five GM1 molecules simultaneously, the binding strength can be increased by at least an order of magnitude[21]
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