Design and in silico screening of inhibitors of the cholera toxin

Abstract

Background: Cholera toxin (CT) is the causative agent for cholera, which is responsible for the death of millions of people. The holotoxin structure of CT in conjunction with its mechanism of action reveals four potential target areas to design CT therapeutic agents: i) the inhibition of adenylate cyclase; ii) the blockage of the active site of the enzyme located in the A subunit; iii) the disruption of the assembly of the holotoxin by interrupting the A2–B interaction; and iv) the interception of the receptor binding to the bottom of the B pentamer. Objective/method: In this review, some of the most exciting and successful CT inhibitors and their design strategies are highlighted. These include transition state analogues and substrate analogues as CTA inhibitors, and pentavalent ligand, sugar-containing dendrimers and sugar mimics as CTB inhibitors. Some recent progress in in silico screening methods is also summarized. Conclusion: The most potent inhibitor demonstrated an IC₅₀ of 50 pM.

Keywords::

• cholera toxin
• GM1
• inhibitor
• multivalency
• substrate analogue
• sugar mimic
• transition state analogue
• virtual screening

Acknowledgements

The author thanks E Fan and W Hol for their discussions on the inhibitor design of cholera toxin, C Verlinde for discussions on computer modeling, and N Angelo for proofreading this manuscript.

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