(A) Model showing the interaction of Ricin toxin A (RTA) with the P stalk to access the sarcin/ricin loop (SRL) of the eukaryotic ribosome. 26S rRNA and 60S subunit are shown in light gray and dark gray, respectively. (B) The 50% inhibitory concentration (IC50) of fragments against RTA.
Ricin toxin is lethal to human at small doses, yet no FDA-approved vaccine or therapeutic exists to protect against ricin poisoning. Ricin inhibits protein synthesis by binding to ribosomes through the ricin toxin A subunit (RTA). To date, developing RTA active site inhibitors as ricin antidotes has not been successful. Therefore, there is great interest and importance in identifying lead compounds that can inhibit RTA-ribosome interactions for the development of potent ricin inhibitors.
Rutgers scientists have used fragment-based lead discovery (FBLD) and surface plasmon resonance (SPR) to discover small molecular weight lead compounds (fragments) with RTA binding affinity in the mid-µM ranges. The interaction of these fragments with RTA has been defined by X-ray crystallography. These compounds are useful for modulating toxin-ribosome interactions and can contribute to the design of the next generation RTA inhibitors with greater potency and selectivity against ricin toxin.
- Efficient FBLD-SPR-based direct screening of small molecules capable of inhibiting RTA-ribosome interactions
- Lower IC50 value (10-100 µM) as compared to that of active site RTA inhibitors (200-2000 µM)
- Development of next generation high affinity RTA inhibitors targeting RTA-ribosome interactions
Intellectual Property & Development Status:
Patent pending. Available for licensing or research collaboration.
Li X-P, Harijan RK, Kahn JN, Schramm VL and Tumer NE. Small molecule inhibitors targeting the interaction of ricin toxin A subunit with ribosomes. ACS Infect. Dis. May 19, 2020.