From the Guidelines
Several peptides can affect NLRP3 inflammasome activation, including MCC950, Oridonin, CY-09, Tranilast, and β-hydroxybutyrate (BHB), with the most recent evidence suggesting that these peptides can prevent the assembly of the inflammasome complex, thereby reducing production of pro-inflammatory cytokines IL-1β and IL-18 1.
Peptides Affecting NLRP3 Activation
The peptides that can affect NLRP3 activation include:
- MCC950, a potent and selective NLRP3 inhibitor that blocks both canonical and non-canonical NLRP3 activation pathways
- Oridonin, which covalently binds to NLRP3 and prevents its interaction with NEK7, inhibiting inflammasome assembly
- CY-09, which directly binds to the ATP-binding motif of NLRP3's NACHT domain, preventing NLRP3 oligomerization
- Tranilast, which inhibits NLRP3 activation by blocking its interaction with BRCC3, a deubiquitinating enzyme
- β-hydroxybutyrate (BHB), a ketone body, which inhibits NLRP3 by preventing potassium efflux and reducing ASC oligomerization
Mechanism of Action
The mechanism of action of these peptides typically involves preventing the assembly of the inflammasome complex, thereby reducing production of pro-inflammatory cytokines IL-1β and IL-18, which are major drivers of inflammation in many diseases 1.
Clinical Significance
These peptides are valuable in treating inflammatory conditions like gout, atherosclerosis, and neurodegenerative diseases where NLRP3 hyperactivation contributes to pathology, and can potentially improve patient outcomes by reducing morbidity, mortality, and improving quality of life 1.
Other Peptides
Other peptides, such as relaxin family peptides, including H1, H2, and H3 relaxin, and INSL3, may also have anti-inflammatory effects, but their role in NLRP3 activation is less clear, and more research is needed to fully understand their potential therapeutic applications 1.
From the Research
Peptides Affecting NLRP3 Activation
- Cell-permeable stapled peptides can inhibit NLRP3 inflammasome activation by targeting the pyrin domain of the adaptor protein ASC, thereby interrupting the development of its filament, which is crucial for NLRP3 inflammasome formation 2
- These peptides can efficiently suppress the release of the inflammasome-regulated cytokines IL-1β and IL-18, following exogenous activation of the NLRP3 inflammasome 2
- The peptides can reduce ASC speck formation and caspase-1 processing, thereby suppressing pro-IL-1β processing and release of active IL-1β 2
Mechanisms of NLRP3 Activation and Inhibition
- Gain-of-function variants in the gene encoding NLRP3 can lead to constitutive inflammasome activation and excessive IL-1β production in cryopyrin-associated periodic syndromes (CAPS) 3
- Structural analysis suggests multiple mechanisms by which CAPS variants activate NLRP3, including enhanced ATP binding, stabilizing the active NLRP3 conformation, destabilizing the inactive NLRP3 complex, and promoting oligomerization of the pyrin domain 3
- NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly, with phosphorylation of NLRP3 S803 controlling NEK7 recruitment to NLRP3 4