细胞因子释放综合征（CRS），通常称为细胞因子风暴，是一种急性全身炎症反应，对全球健康构成重大威胁。白细胞介素 6 (IL-6) 和白细胞介素 1 (IL-1) 是与 CRS 相关的关键促炎细胞因子，因此是关键的治疗靶点。目前的拮抗剂，如托珠单抗和阿那白滞素，以 IL-6R/IL-1R 为靶点，但由于其半衰期长和全身抗炎作用而具有局限性，使其不太适合急性或局部治疗。在这里，我们提出了小蛋白拮抗剂的从头设计，可防止 IL-1 和 IL-6 与其受体相互作用以激活信号传导。设计的蛋白质与 IL-6R、GP130（IL-6 共受体）和 IL-1R1 受体亚基结合，结合亲和力在皮摩尔至低纳摩尔范围内。 X 射线晶体学研究表明，这些拮抗剂的结构与其计算设计模型非常匹配。在人类心脏类器官疾病模型中，IL-1R 拮抗剂表现出对 IL-1β 引起的炎症和心脏损伤的保护作用。这些微型粘合剂有望通过皮下注射或鼻内/吸入途径给药，以减轻急性细胞因子风暴效应。© 2024。作者。

Cytokine release syndrome (CRS), commonly known as cytokine storm, is an acute systemic inflammatory response that is a significant global health threat. Interleukin-6 (IL-6) and interleukin-1 (IL-1) are key pro-inflammatory cytokines involved in CRS and are hence critical therapeutic targets. Current antagonists, such as tocilizumab and anakinra, target IL-6R/IL-1R but have limitations due to their long half-life and systemic anti-inflammatory effects, making them less suitable for acute or localized treatments. Here we present the de novo design of small protein antagonists that prevent IL-1 and IL-6 from interacting with their receptors to activate signaling. The designed proteins bind to the IL-6R, GP130 (an IL-6 co-receptor), and IL-1R1 receptor subunits with binding affinities in the picomolar to low-nanomolar range. X-ray crystallography studies reveal that the structures of these antagonists closely match their computational design models. In a human cardiac organoid disease model, the IL-1R antagonists demonstrated protective effects against inflammation and cardiac damage induced by IL-1β. These minibinders show promise for administration via subcutaneous injection or intranasal/inhaled routes to mitigate acute cytokine storm effects.© 2024. The Author(s).