RICIN-inhibitor design. Final report, 15 April 1993-14 April 1996
Technical Report
·
OSTI ID:415902
The purpose of this proposal was to provide information which will permit the design of transition state inhibitors for ricin A-chain. The original goals were to solve the transition state structure based on kinetic isotope effects. Substrates were synthesized and the conditions for assays optimized to provide catalytic rates at least 1000 fold greater than those published prior to this work. Reliable assay methods have been established to permit routine assays for ricin A-chain. Substrate analogues for N-ribohydrolase reactions have been designed to establish whether the reaction involves leaving-group activation or oxycarbonium ion formation. Based on these results, leaving group activation is a major contributor and oxycarbonium-ion formation is a secondary contribution in the mechanism of catalysis by ricin A-chain. Using this information, the first submicromolar inhibitor of ricin A-chain has been synthesized, tested and kinetically characterized. The development of powerful inhibitors will be a direct extrapolation of these results.
- Research Organization:
- Albert Einstein Coll. of Medicine, Bronx, NY (United States)
- OSTI ID:
- 415902
- Report Number(s):
- AD-A--313750/2/XAB; CNN: Contract DAMD17-93-C-3051
- Country of Publication:
- United States
- Language:
- English
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