Ricin Inhibitors and Methods for Use Thereof
Background Ricin is a potent heterodimeric cytotoxin easily isolated from the seeds of the castor plant, Ricinus communis. The protein consists of a lectin B chain, which can bind cell surfaces and is linked by disulfide bonds to an A chain (RTA), which enzymatically depurinates a key adenine residue in 28 S rRNA. This modification results in devastating cytotoxic effects, rendering Ricin a potent poison agent. Indeed, it has been used as an assassination tool in several well-publicized events.
Given its uses as a bioterrorism agent, there is a need to identify or design potent inhibitors of ricin. Until the present invention, no effective inhibitors for Ricin toxin chain A (RTA) or related Shiga toxin chain A (STA1; produced by Shigella dysenteniae) had been identified. Substrate analogs for the RTA chain have proven ineffective inhibitors of the toxin. New inhibitors need to be identified.
Invention Description Crystallographic studies have revealed the binding specificity of the RTA active site for adenine and other pterin-based ring compounds. STA1 has an active protein chain that is a homologue of RTA, and catalyzes the same depurination reaction. The present invention provides a molecular approach to identify structural elements leading to effective RTA and STA1 inhibition. Further, pterin-ring analogs were identified that can effectively inhibit RTA or STA1 activities. Using these methods, antidotes to ricin or Shiga toxin poisoning can be used for immunotoxin treatment by controlling non-specific cytotoxicity.
Antidotes for ricin or Shiga toxin poisoning Immunotoxin treatment by controlling non-specific cytotoxicity
Molecular approach to RTA and STA1 inhibition Pterin-ring analogs can effectively inhibit RTA and STA1 active sites
IP Status One foreign patent application filed
UT Researcher Sean M. Kerwin, Ph.D., College of Pharmacy, The University of Texas at Austin Jon D. Robertus, Ph.D., Chemistry and Biochemistry, The University of Texas at Austin Xinjian Yan, The University of Texas at Austin
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