What is it about?
Ricin is a Type 2 Ribosome Inactivating Proteins (RIPs) that binds to the Sarcin/Ricin Loop on large ribosomal subunit and inhibits protein synthesis. It is widely produced from the seeds of castor-bean plants. Due to its high availability and extreme toxicity ricin is used as an agent of bioterrorism and currently there are no medications or therapeutic treatments available for ricin poisoning. We have used x-ray crystallography to design small molecules inhibiting the ricin-ribosome interaction and identified RU-NT-204 as the lead compound for drug development. Using Biacore SPR assay and Fluorescence Polarization assay we have shown that RU-NT-204 binds to ribosomal P-stalk protein with equal affinity as that of a five-fold larger P-stalk peptide. This new class of compounds can be further optimized for more potent inhibitor of ricin toxin.
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Why is it important?
Ricin is a plant based toxin that binds to a universally conserved sequence in the P-stalk of eukaryotic ribosomes and prevents protein synthesis. We have developed a structure-based approach to identify a new category of small molecules inhibiting toxin-ribosome interaction. Our lead compound RU-NT-204 bind to the P-stalk proteins with submicromolar affinity and established P-stalk binding site of ricin as a target for allosteric inhibition of it's active site.
Perspectives
I have single-handedly developed the Fluorescence Polarization based competitive displacement assay used in this manuscript to screen small molecules inhibiting the binding of ricin toxin to the conserved C- terminal domain of P-stalk proteins of eukaryotic ribosomes. The assay served as an orthogonal screening technique to the compounds initially selected by Biacore SPR assay and has the potential to be implemented as an HTS technology. I have also purified the RTA subunit of ricin toxin using AKTA purification system.
Dr. ARKAJYOTI DUTTA
Rutgers University New Brunswick
Read the Original
This page is a summary of: Structure-based design and optimization of a new class of small molecule inhibitors targeting the P-stalk binding pocket of ricin, Bioorganic & Medicinal Chemistry, February 2024, Elsevier,
DOI: 10.1016/j.bmc.2024.117614.
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