title: Therapeutic inhibition of pro-inflammatory signaling and toxicity to staphylococcal enterotoxin B by a synthetic dimeric BB-loop mimetic of MyD88.
abstract: Staphylococcal enterotoxin B (SEB) exposure triggers an exaggerated pro-inflammatory cytokine response that often leads to toxic shock syndrome (TSS) associated with organ failure and death. MyD88 mediates pro-inflammatory cytokine signaling induced by SEB exposure and MyD88(-/-) mice are resistant to SEB intoxication, suggesting that MyD88 may be a potential target for therapeutic intervention. We targeted the BB loop region of the Toll/IL-1 receptor (TIR) domain of MyD88 to develop small-molecule therapeutics. Here, we report that a synthetic compound (EM-163), mimic to dimeric form of BB-loop of MyD88 attenuated tumor necrosis factor (TNF)- α, interferon (IFN)-γ, interleukin (IL)-1β, IL-2 and IL-6 production in human primary cells, whether administered pre- or post-SEB exposure. Results from a direct binding assay, and from MyD88 co-transfection/co-immunoprecipitation experiments, suggest that EM-163 inhibits TIR-TIR domain interaction. Additional results indicate that EM-163 prevents MyD88 from mediating downstream signaling. In an NF-kB-driven reporter assay of lipopolysaccharide-stimulated MyD88 signaling, EM-163 demonstrated a dose-dependent inhibition of reporter activity as well as TNF-α and IL-1β production. Importantly, administration of EM-163 pre- or post exposure to a lethal dose of SEB abrogated pro-inflammatory cytokine responses and protected mice from toxic shock-induced death. Taken together, our results suggest that EM-163 exhibits a potential for therapeutic use against SEB intoxication.
authors: Department of Immunology, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors: Teri L
authors: TL
authors: Kissner
authors: Gordon
authors: G
authors: Ruthel
authors: Shahabuddin
authors: S
authors: Alam
authors: Enrique
authors: E
authors: Mann
authors: Dariush
authors: D
authors: Ajami
authors: Mitra
authors: M
authors: Rebek
authors: Eileen
authors: E
authors: Larkin
authors: Stefan
authors: S
authors: Fernandez
authors: Robert G
authors: RG
authors: Ulrich
authors: Sun
authors: S
authors: Ping
authors: David S
authors: DS
authors: Waugh
authors: Julius
authors: J
authors: Rebek
authors: Kamal U
authors: KU
authors: Saikh
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004768:Enterotoxins / Q000633:toxicity*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D016207:Cytokines; D004768:Enterotoxins; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C031818:enterotoxin B, staphylococcal