2. Academic Validation
  3. Discovery of Mycobacterium tuberculosis Rv3364c-Derived Small Molecules as Potential Therapeutic Agents to Target SNX9 for Sepsis

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

  • J Med Chem. 2022 Jan 13;65(1):386-408. doi: 10.1021/acs.jmedchem.1c01551.
Daeun Lee 1,  Eunbi Lee 2 3,  Sein Jang 1 3,  Kyungmin Kim 2 3,  Euni Cho 3 4,  Seok-Jun Mun 3 4,  Wooic Son 1 3,  Hye-In Jeon 1 3,  Hyo Keun Kim 1 3,  Young Jin Jeong 1 3,  Yuno Lee 5,  Ji Eun Oh 6,  Hye Hyun Yoo 6,  Youngbok Lee 2 3 7,  Sun-Joon Min 2 3 7,  Chul-Su Yang 1 3
Affiliations

Affiliations

  • 1 Department of Molecular and Life Science, Hanyang University, Ansan 15588, S. Korea.
  • 2 Department of Applied Chemistry, Hanyang University, Ansan 15588, S. Korea.
  • 3 Center for Bionano Intelligence Education and Research, Ansan 15588, S. Korea.
  • 4 Department of Bionano Technology, Hanyang University, Seoul 04673, S. Korea.
  • 5 Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon 34114, S. Korea.
  • 6 Institute of Pharmaceutical Science and Technology and College of Pharmacy, Hanyang University, Ansan 15588, S. Korea.
  • 7 Department of Chemical & Molecular Engineering, Hanyang University, Ansan 15588, S. Korea.
PMID: 34982557 DOI: 10.1021/acs.jmedchem.1c01551
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.

Figures
Products