Structure-Based Design and Synthesis of a Small Molecule that Exhibits Anti-inflammatory Activity by Inhibition of MyD88-mediated Signaling to Bacterial Toxin Exposure.
Both Gram-positive and Gram-negative pathogens or pathogen-derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88-mediated pro-inflammatory cellular immunity for host defense. However, dysregulated MyD88-mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound 1 mimicking BB-loop structure of MyD88 was capable of inhibiting pro-inflammatory response to SEB exposure in mice. In this study, we designed a dimeric structure compound 4210 covalently linked with compound 1 by a non-polar cyclohexane linker which strongly inhibited the production of pro-inflammatory cytokines in human primary cells to SEB (IC50 1-50 μm) or LPS extracted from Francisella tularensis, Escherichia coli, or Burkholderia mallei (IC50 10-200 μm). Consistent with cytokine inhibition, in a ligand-induced cell-based reporter assay, compound 4210 inhibited Burkholderia mallei or LPS-induced MyD88-mediated NF-kB-dependent expression of reporter activity (IC50 10-30 μm). Furthermore, results from a newly expressed MyD88 revealed that 4210 inhibited MyD88 dimer formation which is critical for pro-inflammatory signaling. Importantly, a single administration of compound 4210 in mice showed complete protection from lethal toxin challenge. Collectively, these results demonstrated that compound 4210 inhibits toxin-induced inflated pro-inflammatory immune signaling, thus displays a potential bacterial toxin therapeutic.
Department of Immunology, Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD, 21702, USA.
Shahabuddin
S
Alam
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Sacha
S
Javor
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Melissa
M
Degardin
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Dariush
D
Ajami
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Mitra
M
Rebek
Department of Immunology, Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD, 21702, USA.
Teri L
TL
Kissner
Department of Immunology, Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD, 21702, USA.
David M
DM
Waag
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Julius
J
Rebek
Department of Immunology, Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD, 21702, USA.
Kamal U
KU
Saikh
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D015195:Drug Design; D004768:Enterotoxins / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004768:Enterotoxins; D053594:Myeloid Differentiation Factor 88; C026066:enterotoxin A, Staphylococcal; C031818:enterotoxin B, staphylococcal
MyD88; cytokine; drug design; inflammation; inhibitors; staphylococcal enterotoxin B; structure based; toxic shock