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Structure-Based Design of Inhibitors to the Cytotoxin Ricin

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Annual rept. 15 Jun 2005-14 Jun 2006

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This contracted project is aimed at designing, synthesizing, and testing small molecule inhibitors of the cytotoxin ricin. Ricin is a class B biological agent which is known to be in the possession of terrorist groups Loyd and Fletcher, 2001. Although not as menacing as infectious agents, ricin is of great concern because of the ease with which large amounts of semi pure material can be produced Wellner, et al, 1995. The Army is proceeding with vaccine development for key military personnel Olson et al, 2004. However, wide spread vaccination of the military or civilian population is not practical or desirable, and so there is a need for an efficacious antidote. In addition to its utility such a compound could reduce panic that arises from a relatively minor terrorist incident. Our area of expertise is the rational design of inhibitors of enzymes like ricin A chain, RTA Miller et al, 2002. We have elucidated the three-dimensional structure of ricin and this model serves as a template for the design of small molecules that can bind tightly and inactivate the toxin. These inhibitor compounds should also incorporate elements of drug design, including solubility, stability, and low toxicity. We have used computer searches to identify classes of inhibitors that act as platform molecules. These platforms have been modified and appended creating novel inhibitors for RTA. This particular project is a collaboration between structural biologists Robertus group and synthetic chemists Kerwin group to extend our previous research efforts on antidotes. It is a step-wise process, beginning with modest inhibitors, which are then sequentially improved after analysis, to produce ever more potent compounds the program is scheduled to last three years.

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  • Chemical, Biological and Radiological Warfare

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