Mycobacterium tuberculosis Rv2626c‐derived peptide as a therapeutic agent for sepsis

EMBO Molecular Medicine

Seok‐Jun Mun¹  Euni Cho¹  Sun Young Kim¹  Sojin Kim²  Chul‐Su Yang²  Daeun Lee²  Wooic Son²  Donggyu Kim²  Kiseok Jang³ 

[1] Department of Bionano Technology Hanyang University Seoul South Korea;Department of Molecular and Life Science Hanyang University Ansan South Korea;Department of Pathology Hanyang University College of Medicine Seoul South Korea;

关键词: macrophage‐targeting;    Mycobacterium tuberculosis Rv2626c peptide;    sepsis;    TRAF6;   

DOI  :  10.15252/emmm.202012497

来源: DOAJ

【 摘 要 】

Abstract The Rv2626c protein of Mycobacterium tuberculosis is a promising vaccine candidate owing to its strong serum antibody response in patients with tuberculosis. However, there is limited information regarding the intracellular response induced by Rv2626c in macrophages. In this study, we demonstrated that Rv2626c interacts with the RING domain of TRAF6 and inhibits lysine (K) 63‐linked polyubiquitination of TRAF6 (E3 ubiquitin ligase activity); this results in the suppression of TLR4 inflammatory signaling in macrophages. Furthermore, we showed that the C‐terminal 123–131‐amino acid Rv2626c motif promotes macrophage recruitment, phagocytosis, M2 macrophage polarization, and subsequent bacterial clearance. We developed rRv2626c‐CA, a conjugated peptide containing the C‐terminal 123–131‐amino acid Rv2626c that targets macrophages, penetrates the cell membrane, and has demonstrated significant therapeutic effects in a mouse model of cecal ligation and puncture‐induced sepsis. This multifunctional rRv2626c‐CA has considerably improved potency, with an IC50 that is 250‐fold (in vitro) or 1,000‐fold (in vivo) lower than that of rRv2626c‐WT. We provide evidence for new peptide‐based drugs with anti‐inflammatory and antibacterial properties for the treatment of sepsis.

【 授权许可】

Unknown