Sepsis and severe inflammatory response syndromes are caused by an over-reaction of the immune system to invasive pathogens. Pathogen-derived microbial pattern recognition motifs activate transmembrane receptors of the Toll-Like-Receptors and Interleukin-1Receptor (TLR/IL-1R) superfamily to mount an inflammatory response of the innate immune system. TLR/IL-1R members initiate intracellular signaling cascades required for host defense by recruiting Myeloid Differentiation factor 88 (MyD88) and MyD88-like adaptor proteins at their intracellular regions. However, uncontrolled activation of the innate immune system can lead to systemic inflammation and excessive collateral damage to host tissues. The IL-1 signaling pathway plays a preeminent role in systemic inflammatory response syndromes and can directly cause widespread endothelial dysfunction, progressive multi-organ failure and death. This proposal intends to modify the immune response and limit collateral damage to the host by blocking the signaling adaptor MyD88. Specifically, MyD88 binds to TLR /IL-1R through its Toll Interleukin Receptor (TIR) domain. The interacting surfaces on the TIR domain of the adaptor and the receptors consist of a conserved hydrophobic sequence (F/Y)-(V/L/I)-(P/G) in a 2-strand conformation. We propose to interfere with MyD88-dependent signaling using synthetic analogues of this interface, called BB-loop mimetics. Lead molecules, with confirmed activity in animal models of fever and LPS- induced acute lung injury, are already in hand and show in vivo efficacy toward the IL- 12 signaling cascade. We propose to further develop these for intervention in systemic inflammatory response syndromes and sepsis:
Aim1 is to synthesize a library of low molecular weight MyD88-TIR domain mimetics in a structure-based approach;
Aim 2 is to further characterize these compounds in cellular models to establish inhibitory selectivity towards TLR/IL-1R signaling; and to examine and optimize pharmacokinetic properties of selected lead compounds;
Aim 3 is to test the potency of lead compounds in preventing lethal systemic inflammatory response syndromes and sepsis. These studies intend to establish a new principle for modifying innate immune signaling through targeting the central adaptor interface of the TLR/IL1R superfamily with small, synthetic compounds. The broader goal is to interrupt inflammatory exacerbation and prevent death in animal models of sepsis.
Sepsis and severe inflammatory response syndromes are caused by an over- reaction of the immune system to invasive pathogens. This research proposes to use small, synthetic compounds to attenuate the immune response. A collection of molecules will be synthesized, tested in cell lines and optimized for their activity in the treatment of sepsis in appropriate animal models.
