Structure-based design and optimization of a new class of small molecule inhibitors targeting the P-stalk binding pocket of ricin.

Autor: Rudolph MJ; New York Structural Biology Center, 89 Convent Ave, New York, NY 10027, United States., Dutta A; Department of Plant Biology, Rutgers, The State University of New Jersey, 59 Dudley Road, New Brunswick, NJ 08901, United States., Tsymbal AM; Molecular Design and Synthesis Core, Rutgers University Biomolecular Innovations Cores, Office for Research, Rutgers University, 610 Taylor Rd, Piscataway, NJ 08854, United States., McLaughlin JE; Department of Plant Biology, Rutgers, The State University of New Jersey, 59 Dudley Road, New Brunswick, NJ 08901, United States., Chen Y; New York Structural Biology Center, 89 Convent Ave, New York, NY 10027, United States., Davis SA; New York Structural Biology Center, 89 Convent Ave, New York, NY 10027, United States., Theodorous SA; New York Structural Biology Center, 89 Convent Ave, New York, NY 10027, United States., Pierce M; Department of Plant Biology, Rutgers, The State University of New Jersey, 59 Dudley Road, New Brunswick, NJ 08901, United States., Algava B; Department of Plant Biology, Rutgers, The State University of New Jersey, 59 Dudley Road, New Brunswick, NJ 08901, United States., Zhang X; Department of Plant Biology, Rutgers, The State University of New Jersey, 59 Dudley Road, New Brunswick, NJ 08901, United States., Szekely Z; Molecular Design and Synthesis Core, Rutgers University Biomolecular Innovations Cores, Office for Research, Rutgers University, 610 Taylor Rd, Piscataway, NJ 08854, United States., Roberge JY; Molecular Design and Synthesis Core, Rutgers University Biomolecular Innovations Cores, Office for Research, Rutgers University, 610 Taylor Rd, Piscataway, NJ 08854, United States., Li XP; Department of Plant Biology, Rutgers, The State University of New Jersey, 59 Dudley Road, New Brunswick, NJ 08901, United States. Electronic address: xpli@sebs.rutgers.edu., Tumer NE; Department of Plant Biology, Rutgers, The State University of New Jersey, 59 Dudley Road, New Brunswick, NJ 08901, United States. Electronic address: tumer@sebs.rutgers.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Feb 15; Vol. 100, pp. 117614. Date of Electronic Publication: 2024 Feb 05.
DOI: 10.1016/j.bmc.2024.117614
Abstrakt: Ricin, a category-B agent for bioterrorism, and Shiga toxins (Stxs), which cause food poisoning bind to the ribosomal P-stalk to depurinate the sarcin/ricin loop. No effective therapy exists for ricin or Stx intoxication. Ribosome binding sites of the toxins have not been targeted by small molecules. We previously identified CC10501, which inhibits toxin activity by binding the P-stalk pocket of ricin toxin A subunit (RTA) remote from the catalytic site. Here, we developed a fluorescence polarization assay and identified a new class of compounds, which bind P-stalk pocket of RTA with higher affinity and inhibit catalytic activity with submicromolar potency. A lead compound, RU-NT-206, bound P-stalk pocket of RTA with similar affinity as a five-fold larger P-stalk peptide and protected cells against ricin and Stx2 holotoxins for the first time. These results validate the P-stalk binding site of RTA as a critical target for allosteric inhibition of the active site.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nilgun Tumer reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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