CGAS inhibitor(Eli Lilly)

Deubiquitinase‐targeting chimera (DUBTAC) is a promising technology for inducing targeted protein stabilization (TPS). Despite its therapeutic potential, very few proteins have been stabilized by DUBTACs to date. The limited applicability of this technology is likely due to the modest DUBTAC‐induced protein stabilization effect, and the scarcity of effective deubiquitinase ligands that can be harnessed for DUBTAC development. Here, we report the discovery of MS7829 and MS8588, the first‐in‐class DUBTACs of cGAS, a key component of the cGAS‐STING pathway. While these DUBTACs are based on a cGAS inhibitor, they effectively stabilized cGAS and activated the cGAS/STING/IRF3 signaling. To develop these cGAS DUBTACs, we optimized EN523, an OTUB1 covalent ligand, into an improved ligand, MS5105. We validated MS5105 by generating a MS5105‐based CFTR DUBTAC, which was approximately 10‐fold more effective in stabilizing the ΔF508‐CFTR mutant protein than the previously reported EN523‐based CFTR DUBTAC. Overall, this work advances the DUBTAC technology for TPS.

Human metapneumovirus(hMPV) is one of the most common viruses that cause acute lower respiratory tract infections. Interleukin-1β (IL-1β) has been reported to play an important role in multiple virus replication. Patients with hMPV infection have increased levels of IL-1β which reminds IL-1β is associated with hMPV infection. However, the mechanism by which IL-1β affects hMPV replication remains unclear. In this study, we explore the effect of IL-1β on hMPV replication and investigate its specific mechanism of action.

We established an hMPV infection model through Human bronchial epithelial cells (16HBE). qRT-PCR and Western Blot were used to detect the expression levels of IL-1β, cyclic GMP-AMP synthase (cGAS), and interferon stimulating factor (STING). Regulating IL-1β expression by small interfering RNA (siRNA) or exogenous supplementary to study the influence of hMPV replication. The selective cGAS inhibitor RU.521, G150, and STING inhibitor H-151 were utilized to detect hMPV replication in 16HBE cells.

The level of IL-1β protein increased in a time-dependent and dose-dependent manner after hMPV infection. The mRNA and protein levels of cGAS and STING were significantly up-regulated. Knockdown of IL-1β could contribute to the decreased viral loads of hMPV. While the exogenous supplement of recombinant human IL-1β in cells, replication of hMPV was significantly increased. Additionally, the level of cGAS-STING protein expression would be affected by regulating IL-1β expression. Inhibitors of the cGAS-STING pathway led to a lower level of hMPV replication.

This study found that IL-1β could promote hMPV replication through the cGAS-STING pathway, which has the potential to serve as a candidate to fight against hMPV infection, targeting IL-1β may be an effective new strategy to restrain virus replication.