# Inhibitors targeting ribosome interactions of ricin

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2020 · $441,113

## Abstract

This proposal brings together investigators from Rutgers University (Tumer, Kimball, Augery),
Albert Einstein College of Medicine (Schramm, Almo and Cameron) and Wadsworth Center
(Mantis) with expertise in biochemistry, structural biology, medicinal chemistry, and toxicology to
identify inhibitors that target ribosome interactions and catalytic activity of ricin. Currently, there
is no proven, safe treatment for ricin intoxication or infection by related Shiga toxin producing
Shigella or E. coli. Two ricin vaccines in clinical trials do not elicit robust toxin neutralizing
activity. The goal of this proposal is to fill this gap by by identifying peptides and small molecule
fragments that bind to key pockets on ricin A chain (RTA) and inhibit its activity. During the
previous funding period we identified the host target of ricin as the conserved C-terminal 11-mer
(P11) of the ribosomal P-protein stalk. We showed that the ribosome binding surface of RTA is
on the opposite face of the active site cleft and proposed a model where binding to the
ribosomal stalk stimulates ribosome depurination by reorienting the active site of RTA towards
the SRL. These studies established a new paradigm for the mechanism of depurination and
identified toxin/ribosome interactions as a new target for inhibitor discovery. We recently
discovered a new hydrophobic pocket anchored by an essential arginine critical for ribosome
interactions of RTA. Our overall hypothesis is that we can inhibit the catalytic activity and the
toxicity of ricin by interfering with ribosome interactions of RTA. We will identify the key
interacting residues at the ribosome binding surface of RTA as a starting point in inhibitor
discovery. Using peptide arrays of the ribosomal target we will identify peptide analogs that bind
to the ribosome binding surface and block the ribosome interactions of RTA. We will use
fragment based lead discovery (FBLD) with surface plasmon resonance (SPR) to identify
fragments that can bind to the ribosome binding pocket, the active site cleft or previously
unidentified pockets and inhibit the depurination activity and toxicity of RTA. Ribosome binding
and active site mutants will be used to determine the binding site selectivity and X-ray crystal
structure analysis will be used to elucidate the binding mode of the peptides and the fragments.
The fragment hits will be optimized and evaluated in cell-based assays and in a mouse model of
ricin intoxication. The promising leads will be used as a starting point to build a scaffold. Our
innovative approach, rigorous methodology and deep insight into the structure function analysis
of RTA will provide new knowledge about the basic mechanism for molecular recognition of the
stalk and will help identify inhibitors that can be used as new leads for future therapeutic design.

## Key facts

- **NIH application ID:** 9851323
- **Project number:** 5R01AI072425-13
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** NILGUN E TUMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,113
- **Award type:** 5
- **Project period:** 2007-03-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851323

## Citation

> US National Institutes of Health, RePORTER application 9851323, Inhibitors targeting ribosome interactions of ricin (5R01AI072425-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851323. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*