Abstract

The continuous emergence of infectious pathogens along with antimicrobial resistance creates a need for an alternative approach to treat infectious diseases. Targeting host factor(s) which are critically involved in immune signaling pathways for modulation of host immunity offers to treat a broad range of infectious diseases. Upon pathogen-associated ligands binding to the Toll-like/ IL-1R family, and other cellular receptors, followed by recruitment of intracellular signaling adaptor proteins, primarily MyD88, trigger the innate immune responses. But activation of host innate immunity strongly depends on the correct function of MyD88 which is tightly regulated. Dysregulation of MyD88 may cause an imbalance that culminates to a wide range of inflammation-associated syndromes and diseases. Furthermore, recent reports also describe that MyD88 upregulation with many viral infections is linked to decreased antiviral type I IFN response, and MyD88-deficient mice showed an increase in survivability. These reports suggest that MyD88 is also negatively involved via MyD88-independent pathways of immune signaling for antiviral type I IFN response. Because of its expanding role in controlling host immune signaling pathways, MyD88 has been recognized as a potential drug target in a broader drug discovery paradigm. Targeting BB-loop of MyD88, small molecule inhibitors were designed by structure-based approach which by blocking TIR–TIR domain homo-dimerization have shown promising therapeutic efficacy in attenuating MyD88-mediated inflammatory impact, and increased antiviral type I IFN response in experimental mouse model of diseases. In this review, we highlight the reports on MyD88-linked immune response and MyD88-targeted therapeutic approach with underlying mechanisms for controlling inflammation and antiviral type I IFN response.

Highlights

• Host innate immunity is activated upon PAMPs binding to PRRs followed by immune signaling through TIR domain–containing adaptor proteins mainly MyD88.

• Structure-based approach led to develop small-molecule inhibitors which block TIR domain homodimerization of MyD88 and showed therapeutic efficacy in limiting severe inflammation-associated impact in mice.

• Therapeutic intervention of MyD88 also showed an increase in antiviral effect with strong type I IFN signaling linked to increased phosphorylation of IRFs via MyD88–independent pathway.

• MyD88 inhibitors might be potentially useful as a small-molecule therapeutics for modulation of host immunity against inflammatory diseases and antiviral therapy.

• However, prior clinical use of more in-depth efforts should be focused for suitability of the approach in deploying to complex diseases including COPD and COVID-19 in limiting inflammation-associated syndrome to infection.

中文翻译：

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MyD88 及其他：调节宿主免疫的 MyD88 靶向治疗方法的视角

摘要

传染性病原体的不断出现以及抗菌素耐药性产生了对治疗传染性疾病的替代方法的需求。靶向与免疫信号通路密切相关的宿主因子来调节宿主免疫，可以治疗多种传染病。当病原体相关配体与 Toll 样/IL-1R 家族和其他细胞受体结合后，细胞内信号转接蛋白（主要是 MyD88）的募集会触发先天免疫反应。但宿主先天免疫的激活很大程度上取决于受到严格调控的MyD88的正确功能。MyD88 失调可能会导致失衡，最终导致多种炎症相关综合征和疾病。此外，最近的报告还描述了许多病毒感染导致的 MyD88 上调与抗病毒 I 型 IFN 反应降低有关，并且 MyD88 缺陷小鼠的生存能力有所提高。这些报告表明，MyD88 还通过独立于 MyD88 的免疫信号通路对抗病毒 I 型 IFN 反应产生负面影响。由于其在控制宿主免疫信号通路方面的作用不断扩大，MyD88 已被认为是更广泛的药物发现范式中的潜在药物靶点。针对 MyD88 的 BB 环，通过基于结构的方法设计了小分子抑制剂，通过阻断 TIR-TIR 结构域同二聚化，在减轻 MyD88 介导的炎症影响和增加实验小鼠的抗病毒 I 型 IFN 反应方面显示出良好的治疗效果疾病模型。在这篇综述中，我们重点介绍了有关 MyD88 相关免疫反应和 MyD88 靶向治疗方法的报告，以及控制炎症和抗病毒 I 型 IFN 反应的潜在机制。

强调

• PAMP 与 PRR 结合后，宿主先天免疫被激活，随后通过包含 TIR 结构域的接头蛋白（主要是 MyD88）发出免疫信号。

• 基于结构的方法导致开发出小分子抑制剂，该抑制剂可阻断 MyD88 的 TIR 结构域同二聚化，并显示出限制小鼠严重炎症相关影响的治疗功效。

• MyD88 的治疗干预还显示出抗病毒作用的增强，这种增强的 I 型 IFN 信号传导与通过 MyD88 独立途径增加 IRF 的磷酸化有关。

• MyD88 抑制剂可能可作为小分子疗法，用于调节宿主对炎症性疾病的免疫力和抗病毒治疗。

• 然而，先前的临床应用应重点关注该方法在复杂疾病（包括 COPD 和 COVID-19）中的适用性，以限制炎症相关综合征的感染。