Structure-Based Design of Inhibitors to the Cytotoxin Ricin
Abstract
Ricin is a cytotoxin and a known bioterrorist weapon. The Army is pursuing anti-ricin vaccines, but plans to develop an efficacious antidote to the toxin, for cases where vaccination is not appropriate. The goal of this project is use the X-ray structure of ricin A chain (RTA) as a template for inhibitor design. Computer modeling and X-ray screening aid in the design process. Inhibitors which bind to the RTA substrate specificity site have been identified. A previous platform, 9-oxoguanine, has been shown to be of limited synthetic utility, however, 9-deaguanine appears to be a more versatile specificity site platform and should allow a range of pendant additions. A search has been initiated to screen for pendants which can be attached to the platform and which make strong and specific interactions at other sites. These groups can aid inhibitor uptake, binding specificity, and binding strength. A new compound, based on aminimide synthesis, was tested just as this report was being prepared. It has an IC50 more than 1000 times as potent as any past inhibitors we have tested; this finding will cause us to modify our research direction to some extent.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2004
- Accession Number
- ADA426876
Entities
People
- Jon D. Robertus
Organizations
- University of Texas at Austin