New covalent inhibitor targets DNAJC9 to reduce sepsis inflammation

This new article publication from Acta Pharmaceutica Sinica B discusses the discovery of the covalent inhibitor A12 and the identification of DNAJC9 as a potential drug target for sepsis-associated inflammation.

Excessive inflammation contributes to organ injury in sepsis, creating a need for new approaches to control the dysregulated immune response. Natural products offer starting points for drug discovery, but their activity and molecular targets often require further investigation. The authors of this article modified tanshinone IIA, a compound found in the medicinal plant Salvia miltiorrhiza, by introducing a chemical group designed to form a covalent bond with a target protein. Screening and structural optimization identified A12, which showed approximately 100-fold greater anti-inflammatory activity than the parent compound and inhibited inflammatory cytokine release at submicromolar concentrations in cell experiments. Oral administration of A12 reduced TNF-α, IL-6, and IL-12 in a lipopolysaccharide-induced mouse model of acute systemic inflammation, while additional experiments showed reduced lung and intestinal injury. A12 also extended the survival window in a cecal ligation and puncture mouse model of sepsis.

Using chemical probes and proteomic analysis, the researchers identified DNAJC9, a co-chaperone in the heat shock protein system, as a direct target. Further experiments showed that A12 forms a covalent bond at DNAJC9's cysteine 243 residue. Reducing DNAJC9 expression also suppressed inflammatory cytokines and diminished the additional effect of A12, supporting the target's role in the compound's activity. The findings link DNAJC9 modulation to nuclear accumulation of HSP70 and suppression of NF-κB inflammatory signaling, although the detailed mechanism requires further investigation. This research identifies a previously unrecognized role for DNAJC9 in inflammation and establishes A12 as a lead compound for further development.

The evidence comes from cell and animal studies; its safety and efficacy in people remain to be established. The proposed application is control of sepsis-associated acute inflammation alongside treatment of the underlying infection.