Touchy-Feely Drug Design

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Science  19 Jul 2002:
Vol. 297, Issue 5580, pp. 303
DOI: 10.1126/science.297.5580.303b

The active agent produced by Vibrio cholerae is cholera toxin, which contains five identical subunits arranged in the form of a pentagon. The toxin pentamer has been the target of studies aimed at designing prophylactic drugs for cholera. It can also serve as a model system for the design of inhibitor molecules that bind to several sites at the same time. If such multivalent inhibitors are optimized for interaction with the pentamer, they should exhibit higher affinity for the toxin than univalent or randomly oriented multivalent molecules.

Earlier, Merritt et al. had described a modular design strategy for synthesizing star-shaped inhibitor molecules consisting of a core, five linkers, and five “fingers” that touch the five binding sites of the toxin. These pentavalent inhibitors did display a higher affinity for the toxin than the corresponding single-site inhibitors. The authors now show that the affinity gain can be increased further through the use of better-fitting fingers, and they also find that the toxins form 1:1 complexes with the inhibitor in solution. The crystal structure of the complex provides more opportunities for improving inhibitor design, especially by tinkering with linkers. — JU

J. Am. Chem. Soc., 10.1021/ja0203560 (2002).

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