Structure Based Design of Cholera Toxin Antagonists

Podlipnik, Črtomir; Reina, José J.

doi:10.5772/37635

“…1 binds with its galactose moiety in the galactose-binding pocket, interacting with Glu51, Gln61, Asn90 and Lys91(Figures 2A,Band 3B). The aryl moiety seems to be disordered in the crystal structure and is not clearly bound in the hydrophobic patch, differing from previous predictions(Podlipnik & Reina, 2012). No clear electron density is visible for the ligand after the peptide bond (Figure 2B).…”

contrasting

confidence: 81%

“…The differences to GM1-osbinding can be seen in the linker region of 2, where the hydrogen bond of the core Gal to the side chain of His13 is no longer achievable, but rather exchanged with a water-mediated connection between the carboxyl of the inhibitor's peptide bond to Asn14(Figure 3A,C). The ligand binding mode was predicted by earlier modeling experiments(Cheshev et al, 2010;Podlipnik & Reina, 2012).…”

mentioning

confidence: 99%

Towards new cholera prophylactics and treatment: Crystal structures of bacterial enterotoxins in complex with GM1 mimics

Heggelund

¹

,

Mackenzie

²

,

Martinsen

³

et al. 2016

Preprint

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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.

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Towards new cholera prophylactics and treatment: Crystal structures of bacterial enterotoxins in complex with GM1 mimics

Heggelund

¹

,

Mackenzie

²

,

Martinsen

³

et al. 2017

Sci Rep

View full text Add to dashboard Cite

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.

show abstract