Synthesis and biological evaluation of Mycobacterium tuberculosis Rv3364c-derived triazine/pyrimidine derivatives as potential therapeutics for sepsis

다국어 초록 (Multilingual Abstract)

Sepsis is a global health problem that affects up to 50 million people each year as a result
of a host response to a bacterial or microbial infection. Although great progress has been
made in the understanding and treatment of sepsis, effective and targeted therapeutic
strategies are still needed. The serine protease inhibitor Rv3364c, secreted from
Mycobacterium tuberculosis (MTB), is highly expressed in cells during MTB exposure.
Rv3364c inhibits the secretion of pro-inflammatory cytokines induced by LPS, a ligand of
toll-like receptors 4 (TLR-4), and binds to the Bin-Amphiphysin-Rvs (BAR) domain of
sorting nexin 9 (SNX9), which is involved in intracellular trafficking. Thus, SNX9 is
crucial in bacterial infection and inflammatory response, which suggests that inhibition of
interaction between SNX9 and its associated protein is a viable molecular target for sepsis.
On the basis of the structure of a key Rv3364c peptide motif (12WLVSKF17) binding to
the BAR domain of SNX9, our drug discovery process, including virtual screening, hit
identification, synthesis and optimization, led to the identification of 4-diamino-6-(4-tertbutylphenyl)-
1,3,5-trazine, DATPT as potential lead compound. Our compound showed
improved potency in in vitro functional assays compared to that of Rv3364c peptide
fragment. Furthermore, it exhibited significant therapeutic effects in a mouse model of
cecal ligation and puncture-induced sepsis.
During the course of lead optimization, compound 22d turned out to be more potent than
DATPT in biochemical assays. The in vivo studies of compound 22d in a mouse model
will be further necessary.
In conclusion, these peptide-derived small molecules will be used as potential lead
compounds for the treatment of sepsis.