title: Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound.
abstract: MyD88 is an adaptor protein, which plays an essential role in the intracellular signaling elicited by IL-1R and several TLRs. Central to its function is the ability of its Toll/IL-1R translation initiation region (TIR) domain to heterodimerize with the receptor and to homodimerize with another MyD88 molecule to favor the recruitment of downstream signaling molecules such as the serine/threonine kinases IL-1R-associated kinase 1 (IRAK1) and IRAK4. Herein, we have synthesized and tested the activity of a synthetic peptido-mimetic compound (ST2825) modeled after the structure of a heptapeptide in the BB-loop of the MyD88-TIR domain, which interferes with MyD88 signaling. ST2825 inhibited MyD88 dimerization in coimmunoprecipitation experiments. This effect was specific for homodimerization of the TIR domains and did not affect homodimerization of the death domains. Moreover, ST2825 interfered with recruitment of IRAK1 and IRAK4 by MyD88, causing inhibition of IL-1beta-mediated activation of NF-kappaB transcriptional activity. After oral administration, ST2825 dose-dependently inhibited IL-1beta-induced production of IL-6 in treated mice. Finally, we observed that ST2825 suppressed B cell proliferation and differentiation into plasma cells in response to CpG-induced activation of TLR9, a receptor that requires MyD88 for intracellular signaling. Our results indicate that ST2825 blocks IL-1R/TLR signaling by interfering with MyD88 homodimerization and suggest that it may have therapeutic potential in treatment of chronic inflammatory diseases.
authors.affiliation: Department of Public Health and Cell Biology, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Loiarro
authors.forename: Federica
authors.initials: F
authors.lastname: Capolunghi
authors.forename: Nicola
authors.initials: N
authors.lastname: Fantò
authors.forename: Grazia
authors.initials: G
authors.lastname: Gallo
authors.forename: Silvia
authors.initials: S
authors.lastname: Campo
authors.forename: Brunilde
authors.initials: B
authors.lastname: Arseni
authors.forename: Rita
authors.initials: R
authors.lastname: Carsetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Carminati
authors.forename: Rita
authors.initials: R
authors.lastname: De Santis
authors.forename: Vito
authors.initials: V
authors.lastname: Ruggiero
authors.forename: Claudio
authors.initials: C
authors.lastname: Sette
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D019281:Dimerization; D005260:Female; D006367:HeLa Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D006574:Heterocyclic Compounds, 2-Ring; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; D017472:Receptors, Interleukin-1; C525002:ST2825; D013141:Spiro Compounds; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C507768:IRAK1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; C507774:Irak4 protein, mouse