Rational design of peptide derivatives for inhibition of MyD88‐mediated toll‐like receptor signaling in human peripheral blood mononuclear cells and epithelial cells exposed to Francisella tularensis |
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Authors: | Daniel A. Ryan Melissa Degardin Shahabuddin Alam Teri L. Kissner Martha Hale Michael D. Cameron Mitra Rebek Dariush Ajami Kamal U. Saikh Julius Rebek Jr |
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Affiliation: | 1. Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA;2. Department of Immunology, Army Medical Research Institute of Infectious Diseases, Frederick, MD, USA;3. Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, USA |
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Abstract: | Small molecules were developed to attenuate proinflammatory cytokines resulting from activation of MyD88‐mediated toll‐like receptor (TLR) signaling by Francisella tularensis. Fifty‐three tripeptide derivatives were synthesized to mimic a key BB‐loop region involved in toll‐like/interleukin‐1 receptor recognition (TIR) domain interactions. Compounds were tested for inhibition of TNF‐α, IFN‐γ, IL‐6, and IL‐1β in human peripheral blood mononuclear cells (PBMCs) and primary human bronchial epithelial cells exposed to LPS extracts from F. tularensis. From 53 compounds synthesized and tested, ten compounds were identified as effective inhibitors of F. tularensisLPS‐induced cytokines. Compound stability testing in the presence of human liver microsomes and human serum resulted in the identification of tripeptide derivative 7 that was a potent, stable, and drug‐like small molecule. Target corroboration using a cell‐based reporter assay and competition experiments with MyD88 TIR domain protein supported that the effect of 7 was through MyD88 TIR domain interactions. Compound 7 also attenuated proinflammatory cytokines in human peripheral blood mononuclear cells and bronchial epithelial cells challenged with a live vaccine strain of F. tularensis at a multiplicity of infection of 1:5. Small molecules that target TIR domain interactions in MyD88‐dependent TLR signaling represent a promising strategy toward host‐directed adjunctive therapeutics for inflammation associated with biothreat agent‐induced sepsis. |
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Keywords: |
Francisella tularensis
MyD88 proinflammatory cytokines sepsis TIR domain inhibitors TLR signaling inhibitors |
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