| Autor: |
Mohd, Abdullaha, Mehboob, Ali, Dilpreet, Kour, Ramesh, Mudududdla, Parul, Khajuria, Ajay, Kumar, Sandip B, Bharate |
| Rok vydání: |
2021 |
| Zdroj: |
ACS Pharmacol Transl Sci |
| ISSN: |
2575-9108 |
| Popis: |
[Image: see text] Nucleotide-binding domain leucine-rich repeat family pyrin domain containing 3 (NLRP3) inflammasome complex regulates the caspase-1 activity and subsequent processing of interleukin-1β (IL-1β). Various inflammatory diseases involve the activation of inflammasome complexes; thus, the intervention in complex formation via small molecules offers a new therapeutic opportunity. The structure-guided design and synthesis of a series of methoxystilbenes and methoxy-2-phenylnaphthalenes identified new inhibitors of NLRP3 inflammasome complex. The tetramethoxystilbene 4o and trimethoxy 2-phenylnaphthalene 1t inhibit the release of a mature form of IL-1β in J774A.1 cells with IC(50) values of 1.39 and 2.07 μM, respectively. Mechanistic investigation revealed that tetramethoxystilbene 4o blocks the oligomerization of apoptosis-associated speck-like protein (ASC), which is the vital step in the formation of NLRP3 inflammasome assembly, thus preventing the activation of caspase-1 and the IL-1β release. Treatment of LPS+ATP challenged mice with 20 mg/kg of 4o significantly suppressed the levels of IL-1β. The data presented herein warrant further investigation of methoxystilbenes in disease-specific models of inflammatory diseases. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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