Sepsis is a lethal host response to microbial infection, and an imbalance of inflammatory mediators leads to high mortality. Its common symptoms include fever, arrhythmias, and heart failure. Our understanding the pathogenesis of sepsis has progressed, but finding effective therapeutic targets is still highly requested. Mycobacterium tuberculosis (MTB) Rv3364c, known as serine protease inhibitor, is one of the highly expressed proteins in cells during MTB infection. A hexapeptide fragment WLVSKF, derived from Rv3364c inhibits the BAR domain of SNX9 that interacts with p47phox in the endosome, which negatively regulates TLR4 inflammatory signaling pathway in macrophages. On the basis of the structure of this Rv3364c peptide motif, our drug discovery process including virtual screening, hit identification, synthesis and optimization led to identification of 2,4-diamino-6-(4-tert-butylphenyl)-1,3,5-trazine as peptide-mimetic small molecule. In in-vitro assays, our compound not only inhibit the SNX9-p47phox interaction in endosome, but also reduces reactive oxygen species and inflammatory cytokine production. Furthermore, we showed that our compound protects mice from CLP-induced polymicrobial sepsis with high potency. Interestingly, we found that this molecule showed potent anti-bacterial activities through reduction of ATP production, which is presumably induced by leakage of intracellular ATP out of bacteria via membrane disrupture. In this presentation, we will provide our discovery process of peptide-derived small molecule targeting SNX9-p47phox interaction for the treatment of sepsis.

Identification of Mycobacterium tuberculosis Rv3364c-derived triazine derivatives as SNX9 inhibitors for treatment of sepsis

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.