Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection

TANK-binding kinase 1 (TBK1) is a key signalling component in the production of type-I interferons, which have essential antiviral activities, including against SARS-CoV-2. TBK1, and its homologue IκB kinase-ε (IKKε), can also induce pro-inflammatory responses that contribute to pathogen clearance. While initially protective, sustained engagement of type-I interferons is associated with damaging hyper-inflammation found in severe COVID-19 patients. The contribution of TBK1/IKKε signalling to these responses is unknown. Here we find that the small molecule idronoxil inhibits TBK1/IKKε signalling through destabilisation of TBK1/IKKε protein complexes. Treatment with idronoxil, or the small molecule inhibitor MRT67307, suppresses TBK1/IKKε signalling and attenuates cellular and molecular lung inflammation in SARS-CoV-2-challenged mice. Our findings additionally demonstrate that engagement of STING is not the major driver of these inflammatory responses and establish a critical role for TBK1/IKKε signalling in SARS-CoV-2 hyper-inflammation.

 

Comments:

It seems like you've provided a detailed description of a scientific study or research findings related to the role of Tank-binding kinase 1 (TBK1) and its homologue IκB kinase-ε (IKKε) in the context of SARS-CoV-2 infection. The study suggests that TBK1/IKKε signaling plays a significant role in the production of type-I interferons and pro-inflammatory responses, both of which are essential for antiviral activities. However, sustained engagement of type-I interferons can lead to damaging hyper-inflammation seen in severe COVID-19 cases.

The study indicates that a small molecule called idronoxil inhibits TBK1/IKKε signaling by destabilizing TBK1/IKKε protein complexes. Additionally, another small molecule inhibitor called MRT67307 has similar effects. Treatment with these inhibitors suppresses TBK1/IKKε signaling and reduces lung inflammation in mice challenged with SARS-CoV-2. The study also suggests that the engagement of STING (Stimulator of Interferon Genes) is not the main driver of these inflammatory responses, highlighting the critical role of TBK1/IKKε signaling in SARS-CoV-2 hyper-inflammation.

This research provides valuable insights into the molecular mechanisms underlying the inflammatory responses in severe COVID-19 cases and suggests potential therapeutic targets for mitigating hyper-inflammation associated with the disease.

Related Products

Cat.No.	Product Name	Information
S7948	MRT67307 HCl	MRT67307 is a potent and dual IKKϵ and TBK1 inhibitor with IC50 of 160 and 19 nM, respectively. MRT67307 potently inhibits ULK1 and ULK2 and blocks autophagy.

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IκB/IKK TBK1 Autophagy ULK