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Baicalin inhibits the lethality of ricin in mice by inducing protein oligomerization
Jing Dong1, Yong Zhang2, Yutao Chen3
1From the Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, the Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan 430223.
Abstract:
Toxic ribosome-inactivating proteins abolish cell viability by inhibiting protein synthesis. Ricin, a member of these lethal proteins, is a potential bioterrorism agent. Despite the grave challenge posed by these toxins to public health, post-exposure treatment for intoxication caused by these agents currently is unavailable. In this study, we report the identification of baicalin extracted from Chinese herbal medicine as a compound capable of inhibiting the activity of ricin. More importantly, post-exposure treatment with baicalin significantly increased the survival of mice poisoned by ricin. We determined the mechanism of action of baicalin by solving the crystal structure of its complex with the A chain of ricin (RTA) at 2.2 Å resolution, which revealed that baicalin interacts with two RTA molecules at a novel binding site by hydrogen bond networks and electrostatic force interactions, suggesting its role as molecular glue of the RTA. Further biochemical and biophysical analyses validated the amino acids directly involved in binding the inhibitor, which is consistent with the hypothesis that baicalin exerts its inhibitory effects by inducing RTA to form oligomers in solution, a mechanism that is distinctly different from previously reported inhibitors. This work offers promising leads for the development of therapeutics against ricin and probably other ribosome-inactivating proteins.
Insights
Baicalin, from Chinese herbal medicine, inhibits ricin toxin activity. Post-exposure treatment with baicalin significantly improved survival in mice poisoned by ricin, offering a potential therapeutic strategy.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Ribosome-inactivating proteins (RIPs) are toxic compounds that inhibit protein synthesis, leading to cell death.
- Ricin, a potent RIP, poses a significant bioterrorism threat, yet no effective post-exposure treatments exist.
- Current therapeutic options for ricin intoxication are limited, highlighting an urgent need for novel interventions.
Purpose of the Study:
- To identify compounds that can inhibit ricin activity and serve as post-exposure treatments.
- To elucidate the mechanism of action of identified inhibitors at a molecular level.
- To evaluate the therapeutic potential of baicalin against ricin intoxication in a preclinical model.
Main Methods:
- Crystal structure determination of baicalin complexed with ricin A chain (RTA) at 2.2 Å resolution.
- Biochemical and biophysical analyses to validate binding interactions and identify key amino acids.
- In vivo studies assessing the efficacy of post-exposure baicalin treatment in a mouse model of ricin poisoning.
Main Results:
- Baicalin was identified as a novel inhibitor of ricin activity, extracted from Chinese herbal medicine.
- Structural analysis revealed baicalin binds to RTA at a unique site, forming hydrogen bonds and electrostatic interactions, potentially acting as a molecular glue.
- Baicalin treatment significantly increased the survival rate of ricin-intoxicated mice.
- Mechanism involves inducing RTA oligomerization, distinct from other known inhibitors.
Conclusions:
- Baicalin demonstrates significant therapeutic potential as a post-exposure treatment for ricin intoxication.
- The novel mechanism of action, inducing RTA oligomerization, provides new insights into RIP inhibition.
- This study offers promising leads for developing therapeutics against ricin and potentially other ribosome-inactivating proteins.
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