2. Academic Validation
  3. ECDD-S16 targets vacuolar ATPase: A potential inhibitor compound for pyroptosis-induced inflammation

ECDD-S16 targets vacuolar ATPase: A potential inhibitor compound for pyroptosis-induced inflammation

  • PLoS One. 2023 Nov 27;18(11):e0292340. doi: 10.1371/journal.pone.0292340.
Peeraya Ekchariyawat 1,  Rattatammanoon Saengfak 2,  Sucharat Sanongkiet 3,  Thanapon Charoenwongpaiboon 3,  Suphasuta Khongpraphan 2,  Supaporn Mala 4,  Chularat Luangjindarat 2,  Bumrung Munyoo 5,  Napason Chabang 6,  Sitthivut Charoensutthivarakul 5 6 7,  Suparerk Borwornpinyo 5 8,  Patoomratana Tuchinda 5,  Marisa Ponpuak 2,  Matsayapan Pudla 9,  Pongsak Utaisincharoen 2
Affiliations

Affiliations

  • 1 Department of Microbiology, Faculty of Public Health, Mahidol University, Bangkok, Thailand.
  • 2 Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 3 Department of Chemistry, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand.
  • 4 Research Office, Faculty of Dentistry, Mahidol University, Bangkok, Thailand.
  • 5 Excellence Center for Drug Discovery (ECDD), Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 6 School of Bioinnovation and Bio-Based Product Intelligence, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 7 Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 8 Department of Biotechnology, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • 9 Department of Oral Microbiology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand.
PMID: 38011122 DOI: 10.1371/journal.pone.0292340
Abstract

Background: Cleistanthin A (CA), extracted from Phyllanthus taxodiifolius Beille, was previously reported as a potential V-ATPase inhibitor relevant to Cancer cell survival. In the present study, ECDD-S16, a derivative of cleistanthin A, was investigated and found to interfere with Pyroptosis induction via V-ATPase inhibition.

Objective: This study examined the ability of ECDD-S16 to inhibit endolysosome acidification leading to the attenuation of Pyroptosis in Raw264.7 macrophages activated by both surface and endosomal TLR ligands.

Methods: To elucidate the activity of ECDD-S16 on pyroptosis-induced inflammation, Raw264.7 cells were pretreated with the compound before stimulation with surface and endosomal TLR ligands. The release of Lactate Dehydrogenase (LDH) was determined by LDH assay. Additionally, the production of cytokines and the expression of Pyroptosis markers were examined by ELISA and immunoblotting. Moreover, molecular docking was performed to demonstrate the binding of ECDD-S16 to the vacuolar (V-)ATPase.

Results: This study showed that ECDD-S16 could inhibit Pyroptosis in Raw264.7 cells activated with surface and endosomal TLR ligands. The attenuation of Pyroptosis by ECDD-S16 was due to the impairment of endosome acidification, which also led to decreased Reactive Oxygen Species (ROS) production. Furthermore, molecular docking also showed the possibility of inhibiting endosome acidification by the binding of ECDD-S16 to the vacuolar (V-)ATPase in the region of V0.

Conclusion: Our findings indicate the potential of ECDD-S16 for inhibiting Pyroptosis and prove that vacuolar H+ ATPase is essential for Pyroptosis induced by TLR ligands.

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