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Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy

The p38MAPK-MK2 signaling axis functions as an initiator of inflammation. Targeting the p38MAPK-MK2 signaling axis represents a direct therapeutic intervention of inflammatory diseases. We described here a novel role of andrographolide (AG), a small-molecule ent-labdane natural compound, as an inhibitor of p38MAPK-MK2 axis via MK2 degradation. AG was found to bind to the activation loop of MK2, located at the interface of the p38MAPK-MK2 biomolecular complex. This interaction disrupted the complex formation and predisposed MK2 to proteasome-mediated degradation. We showed that AG induced MK2 degradation in a concentration- and time-dependent manner and exerted its anti-inflammatory effects by enhancing the mRNA-destabilizing activity of tristetraprolin, thereby inhibiting pro-inflammatory mediator production (e.g., TNF-α, MCP-1). Administration of AG via intratracheal (i.t.) route to mice induced MK2 downregulation in lung alveolar macrophages, but not lung tissues, and prevented macrophage activation. Our study also demonstrated that the anti-inflammatory effects achieved by AG via MK2 degradation were more durable and sustained than that achieved by the conventional MK2 kinase inhibitors (e.g., PF-3644022). Taken together, our findings illustrated a novel mode of action of AG by modulating the p38MAPK-MK2 signaling axis and would pave the way for the development of a novel class of anti-inflammatory agents targeting MK2 for degradation by harnessing the privileged scaffold of AG.

 

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The passage you provided describes a study that investigated the potential anti-inflammatory effects of andrographolide (AG), a natural compound, by targeting the p38MAPK-MK2 signaling axis. Here's a breakdown of the key points:

1. **Background Information:**
   - The p38MAPK-MK2 signaling axis is implicated in initiating inflammation.
   - Targeting this signaling axis is considered a direct therapeutic approach for inflammatory diseases.

2. **Andrographolide (AG) as an Inhibitor:**
   - AG is described as a small-molecule ent-labdane natural compound.
   - It acts as an inhibitor of the p38MAPK-MK2 axis by promoting the degradation of MK2.

3. **Mechanism of Action:**
   - AG was found to bind to the activation loop of MK2, disrupting the biomolecular complex between p38MAPK and MK2.
   - This interaction leads to the proteasome-mediated degradation of MK2.

4. **Effects on Inflammation:**
   - AG induces concentration- and time-dependent degradation of MK2.
   - The anti-inflammatory effects of AG are attributed to the enhancement of mRNA-destabilizing activity of tristetraprolin, which inhibits the production of pro-inflammatory mediators like TNF-α and MCP-1.

5. **In Vivo Study:**
   - Administration of AG via intratracheal (i.t.) route to mice results in MK2 downregulation in lung alveolar macrophages.
   - This downregulation in MK2 prevents macrophage activation.

6. **Comparison with Conventional Inhibitors:**
   - The study suggests that the anti-inflammatory effects achieved by AG through MK2 degradation are more durable and sustained compared to conventional MK2 kinase inhibitors like PF-3644022.

7. **Conclusion:**
   - The findings propose a novel mode of action for AG in modulating the p38MAPK-MK2 signaling axis.
   - This could pave the way for the development of a new class of anti-inflammatory agents that target MK2 for degradation, utilizing the unique properties of AG.

In summary, the study suggests that andrographolide may have therapeutic potential for inflammatory diseases by specifically targeting and degrading MK2 within the p38MAPK-MK2 signaling axis. This could offer a new approach with potential advantages over existing treatments.

Related Products

Cat.No. Product Name Information
S8224 PF-3644022

PF-3644022 is a potent freely reversible ATP-competitive inhibitor of MAPKAPK2 (MK2) with an Ki of 3 nM. PF-3644022 also potently inhibits TNFα production with an IC50 of 160 nM.

Related Targets

MAPKAPK2 TNF-alpha