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Discovery of Mycobacterium tuberculosis Rv3364c-Derived Small Molecules as Potential Therapeutic Agents to Target SNX9 for Sepsis

Authors
Lee, DaeunLee, EunbiJang, SeinKim, KyungminCho, EuniMun, Seok-JunSon, WooicJeon, Hye-InKim, Hyo KeunJeong, Young JinLee, YunoOh, Ji EunYoo, Hye HyunLee, YoungbokMin, Sun-JoonYang, Chul-Su
Issue Date
Jan-2022
Publisher
American Chemical Society
Citation
Journal of Medicinal Chemistry, v.65, no.1, pp.386 - 408
Indexed
SCIE
SCOPUS
Journal Title
Journal of Medicinal Chemistry
Volume
65
Number
1
Start Page
386
End Page
408
URI
https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/108021
DOI
10.1021/acs.jmedchem.1c01551
ISSN
0022-2623
Abstract
The serine protease inhibitor Rv3364c of Mycobacterium tuberculosis (MTB) is highly expressed in cells during MTB exposure. In this study, we showed that the 12WLVSKF17 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-tert-butylphenyl)-1,3,5-trazine, DATPT as a 12WLVSKF17 peptide-mimetic small molecule has been identified. DATPT 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. DATPT has considerably improved potency, with an IC50 500-fold (in vitro) or 2000-fold (in vivo) lower than that of the 12WLVSKF17 peptide. Furthermore, DATPT 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 DATPT with anti-inflammatory and antibacterial functions for the treatment of sepsis.
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COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY > ERICA 의약생명과학과 > 1. Journal Articles
COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY > DEPARTMENT OF CHEMICAL AND MOLECULAR ENGINEERING > 1. Journal Articles

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Yang, Chul Su
ERICA 과학기술융합대학 (ERICA 의약생명과학과)
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