Discovery of Mycobacterium tuberculosis Rv3364c-Derived Small Molecules as Potential Therapeutic Agents to Target SNX9 for Sepsis
- Title
- Discovery of Mycobacterium tuberculosis Rv3364c-Derived Small Molecules as Potential Therapeutic Agents to Target SNX9 for Sepsis
- Author
- 민선준
- Issue Date
- 2022-01
- Publisher
- AMER CHEMICAL SOC
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY, v. 65, NO 1, Page. 386-408
- 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.
- URI
- https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01551https://repository.hanyang.ac.kr/handle/20.500.11754/171086
- ISSN
- 00222623; 15204804
- DOI
- 10.1021/acs.jmedchem.1c01551
- Appears in Collections:
- COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY[E](과학기술융합대학) > CHEMICAL AND MOLECULAR ENGINEERING(화학분자공학과) > Articles
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