Discovery of <i>Mycobacterium tuberculosis</i> Rv3364c-Derived Small Molecules as Potential Therapeutic Agents to Target SNX9 for Sepsis.
Lee D, Lee E, Jang S, Kim K, Cho E, Mun SJ, Son W, Jeon HI, Kim HK, Jeong YJ, Lee Y, Oh JE, Yoo HH, Lee Y, Min SJ, Yang CS.
The serine protease inhibitor Rv3364c of <i>Mycobacterium tuberculosis</i> (MTB) is highly expressed in cells during MTB exposure. In this study, we showed that the <sub>12</sub>WLVSKF<sub>17</sub> motif of Rv3364c interacts with the BAR domain of SNX9 and inhibits endosome trafficking to interact with p47phox, thereby suppressing TLR4 inflammatory signaling in macrophages. Derived from the structure of this Rv3364c peptide motif, 2,4-diamino-6-(4-<i>tert</i>-butylphenyl)-1,3,5-trazine, <b>DATPT</b> as a <sub>12</sub>WLVSKF<sub>17</sub> peptide-mimetic small molecule has been identified. <b>DATPT</b> can block the SNX9-p47phox interaction in the endosome and suppress reactive oxygen species and inflammatory cytokine production; it demonstrated significant therapeutic effects in a mouse model of cecal ligation and puncture-induced sepsis. <b>DATPT</b> has considerably improved potency, with an IC<sub>50</sub> 500-fold (<i>in vitro</i>) or 2000-fold (<i>in vivo</i>) lower than that of the <sub>12</sub>WLVSKF<sub>17</sub> peptide. Furthermore, <b>DATPT</b> shows potent antibacterial activities by reduction in ATP production and leakage of intracellular ATP out of bacteria. These results provide evidence for peptide-derived small molecule <b>DATPT</b> with anti-inflammatory and antibacterial functions for the treatment of sepsis.