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PROTAC targeting cyclophilin A controls virus-induced cytokine storm

Cytokine storms caused by viruses are associated with elevated cytokine levels and uncontrolled inflammatory responses that can lead to acute respiratory distress syndrome. Current antiviral therapies are not sufficient to prevent or treat these complications. Cyclophilin A (CypA) is a key factor that regulates the production of multiple cytokines and could be a potential therapeutic target for cytokine storms. Here, three proteolysis targeting chimeras (PROTACs) targeting CypA were designed. These PROTACs bind to CypA, enhance its ubiquitination, and promote its degradation in both cell lines and mouse organs. During influenza B virus (IBV) infection, PROTAC-mediated CypA depletion reduces P65 phosphorylation and NF-κB-mediated proinflammatory cytokine production in A549 cells. Moreover, Comp-K targeting CypA suppresses excessive secretion of proinflammatory cytokines in bronchoalveolar lavage fluid, reduces lung injury, and enhances survival rates of IBV-infected mice. Collectively, we provide PROTACs targeting CypA, which are potential candidates for the control of cytokine storms.

 

Comments:

This sounds like an exciting development in the field of virology and immunology! Targeting Cyclophilin A (CypA) with proteolysis targeting chimeras (PROTACs) seems to offer a promising avenue for managing cytokine storms associated with viral infections like influenza B virus (IBV).

The ability of these PROTACs to bind to CypA, enhance its ubiquitination, and facilitate its degradation holds significant therapeutic potential. By reducing CypA levels, these compounds appear to modulate NF-κB-mediated proinflammatory cytokine production, ultimately mitigating the exaggerated immune response responsible for the cytokine storm and subsequent tissue damage.

The evidence showing reduced P65 phosphorylation and decreased proinflammatory cytokine secretion in both cell lines and mouse models during IBV infection is particularly promising. Moreover, the observed reduction in lung injury and enhanced survival rates in IBV-infected mice after treatment with Comp-K targeting CypA underscore the potential clinical relevance of these findings.

Developing targeted therapies like PROTACs that specifically address the dysregulated immune responses associated with cytokine storms could significantly improve outcomes for patients suffering from severe viral infections. This research might pave the way for more effective treatments to manage these life-threatening complications.

Do you have any specific questions about this exciting development, or is there anything else you'd like to discuss regarding cytokine storms or targeted therapies for viral infections?

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E1161 CompK CompK (compound K), a potent and selective hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) small molecule inhibitor, significantly improves human T-cell functions, with enhanced T-cell receptor avidity to recognize tumor-associated antigens and tumor cytolytic activity by CD8+ T cells.

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MAP4K