title: The targeted delivery of the c-Src peptide complexed with schizophyllan to macrophages inhibits polymicrobial sepsis and ulcerative colitis in mice.
abstract: Hyper-inflammatory responses triggered by intracellular reactive oxygen species (ROS) can lead to a variety of diseases, including sepsis and colitis. However, the regulators of this process remain poorly defined. In this study, we demonstrate that c-Src is a negative regulator of cellular ROS generation through its binding to p47phox. This molecule also competitively inhibits the NADPH oxidase complex (NOX) assembly. Furthermore, we developed the schizophyllan (SPG)-c-Src SH3 peptide, which is a β-1,3-glucan conjugated c-Src SH3-derived peptide composed of amino acids 91-108 and 121-140 of c-Src. The SPG-SH3 peptide has a significant therapeutic effect on mouse ROS-mediated inflammatory disease models, cecal-ligation-puncture-induced sepsis, and dextran sodium sulfate-induced colitis. It does so by inhibiting the NOX subunit assembly and proinflammatory mediator production. Therefore, the SPG-SH3 peptide is a potential therapeutic agent for ROS-associated lethal inflammatory diseases. Our findings provide clues for the development of new peptide-base drugs that will target p47phox.
authors.affiliation: Department of Molecular and Life Science, Hanyang University, Ansan 15588, Republic of Korea.
authors.forename: Ye-Ram
authors.initials: YR
authors.lastname: Kim
authors.affiliation: School of Integrative Engineering, Chung-Ang University, Seoul 06974, Republic of Korea.
authors.forename: Jangsun
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Molecular and Life Science, Hanyang University, Ansan 15588, Republic of Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Koh
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea.
authors.forename: Kiseok
authors.initials: K
authors.lastname: Jang
authors.affiliation: QueGen Biotech, Siheung 15097, Republic of Korea.
authors.forename: Jong-Dae
authors.initials: JD
authors.lastname: Lee
authors.affiliation: School of Integrative Engineering, Chung-Ang University, Seoul 06974, Republic of Korea. Electronic address: jonghchoi@gmail.com.
authors.forename: Jonghoon
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Molecular and Life Science, Hanyang University, Ansan 15588, Republic of Korea. Electronic address: chulsuyang@hanyang.ac.kr.
authors.forename: Chul-Su
authors.initials: CS
authors.lastname: Yang
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D016503:Drug Delivery Systems; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000276:immunology; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000276:immunology; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D012566:Sizofiran / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000276:Adjuvants, Immunologic; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C040475:Src peptide; D012566:Sizofiran; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
keywords: Colitis; Reactive oxygen species; Schizophyllan; Sepsis; c-Src