Ricin is a heterodimeric, toxic protein that can be easily isolated from Ricinus
communis (castor seeds). It consists of a B-chain lectin (RTB) and an A-chain enzyme (RTA).
RTB aids in cell surface binding and increase the efficiency of endocytotic uptake of ricin.
Once in the cell, RTA attacks ribosomes, removing a specific adenine base from the 28S rRNA and
thereby inhibiting protein synthesis. Ricin is extremely cytotoxic, and the toxic dose for humans
is likely to be in the ?g/kg range, making ricin one of the most toxic substances known. It is
therefore important to develop inhibitors of the toxin which might be used as antidotes to ricin
poisoning.
In collaboration with the group of Prof. Jon D. Robertus in the Department of Chemistry and Biochemistry,
we are employing structure-based design methods to design inhibitors for ricin. Using the x-ray crystal
structure of RTA and the molecular modeling package CHEM-X, over 250,000 compounds in the NCI database
were screened as potential inhibitors. This resulted in the identification of pteroic acid and modified
guanine molecules as weak RTA inhibitors. These compounds bind in the RTA "specificity pocket", a cleft
formed upon substrate binding which contacts the adenine base.
In order to develop more potent inhibitors than those currently available, we began a systematic design
of potential RTA specificity pocket ligands. Our initial results show that 8-methyl-9-oxoguanine inhibits
RTA by binding to the specificity pocket. Although the inhibition constant for 8-methyl-9-oxoguanine is only
400 µM, we are constructing analogs containing more suitable side chains at the8-position that we believe
will be much more effective inhibitors.
X-ray crystal structure of 8-methyl-9-oxoguanine (ball-and-stick model) bound to
RTA.
For more information on ricin inhibitors, see the following publications:
- Yan, X.; Hollis, T.; Svinth, M.; Day, P.; Monzingo, A. F.; Milne, G. W. A.;
Robertus, J. D. Structure-based identification of a Ricin inhibitor. J. Mol. Biol 1997, 266, 1043-1049
- Miller, D. J.; Ravikumar, K. S.; Shen, H.; Suh, J. K.; Kerwin, S. M.; Robertus, J. D. Structure-Based Design and
Characterization of Novel Platforms for Ricin and Shiga Toxin Inhibition. J. Med. Chem. 2002, 45, 90-98.
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23 February 2005
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