用于体内缺血/再灌注损伤治疗的抗 HMGB1 合成抗体的设计,Journal of the American Chemical Society

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用于体内缺血/再灌注损伤治疗的抗 HMGB1 合成抗体的设计
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-10-16 , DOI: 10.1021/jacs.3c06799
Hiroyuki Koide ₁ , Chiaki Kiyokawa ₁ , Anna Okishima ₁ , Kaito Saito ₁ , Keiichi Yoshimatsu ₂ , Tatsuya Fukuta ₁ , Yu Hoshino ₃ , Tomohiro Asai ₁ , Yuri Nishimura ₃ , Yoshiko Miura ₃ , Naoto Oku ₁ , Kenneth J Shea ₄

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高迁移率族蛋白 1 (HMGB1) 是一种多功能蛋白。受伤或感染后，HMGB1 从坏死和活化的树突状细胞和巨噬细胞中被动释放，充当细胞因子，充当 RAGE 的配体，RAGE 是先天免疫刺激炎症反应的主要受体，包括脑缺血/再灌注的发病机制。 I/R) 损伤。阻断 HMGB1/RAGE 轴为治疗这些炎症提供了一种治疗方法。在这里，我们描述了一种合成抗体 ( SA )，一种结合 HMGB1 的共聚物纳米颗粒 (NP)。从含有三硫酸化 3,4,6S-GlcNAc 和疏水性N-叔丁基丙烯酰胺 (TBAm) 单体的小型库中选择对 HMGB1 具有纳摩尔亲和力的轻度交联的N-异丙基丙烯酰胺 (NIPAm) 水凝胶共聚物。肝素竞争性结合实验证实， SA和 HMGB1之间的主要相互作用发生在肝素结合域。体外研究表明，抗 HMGB1- SA可抑制 HUVEC 的 HMGB1 依赖性 ICAM-1 表达和 ERK 磷酸化，从而证实SA与 HMGB1 结合可抑制该蛋白与 RAGE 受体的相互作用。使用临时大脑中动脉闭塞（t-MCAO）模型大鼠，发现抗 HMGB1- SA通过穿过血脑屏障在缺血脑中积聚。值得注意的是，对 t-MCAO 大鼠施用抗 HMGB1- SA显着减少了脑缺血/再灌注引起的脑损伤。这些结果表明，从使用功能单体的“知情”选择合成的小型候选物库中选出的统计共聚物可以产生功能性合成抗体。从这些实验中获得的知识可以促进新类别药物的发现、设计和开发。

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Design of an Anti-HMGB1 Synthetic Antibody for In Vivo Ischemic/Reperfusion Injury Therapy

High-mobility group box 1 (HMGB1) is a multifunctional protein. Upon injury or infection, HMGB1 is passively released from necrotic and activated dendritic cells and macrophages, where it functions as a cytokine, acting as a ligand for RAGE, a major receptor of innate immunity stimulating inflammation responses including the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Blocking the HMGB1/RAGE axis offers a therapeutic approach to treating these inflammatory conditions. Here, we describe a synthetic antibody (SA), a copolymer nanoparticle (NP) that binds HMGB1. A lightly cross-linked N-isopropylacrylamide (NIPAm) hydrogel copolymer with nanomolar affinity for HMGB1 was selected from a small library containing trisulfated 3,4,6S-GlcNAc and hydrophobic N-tert-butylacrylamide (TBAm) monomers. Competition binding experiments with heparin established that the dominant interaction between SA and HMGB1 occurs at the heparin-binding domain. In vitro studies established that anti-HMGB1-SA inhibits HMGB1-dependent ICAM-1 expression and ERK phosphorylation of HUVECs, confirming that SA binding to HMGB1 inhibits the proteins’ interaction with the RAGE receptor. Using temporary middle cerebral artery occlusion (t-MCAO) model rats, anti-HMGB1-SA was found to accumulate in the ischemic brain by crossing the blood–brain barrier. Significantly, administration of anti-HMGB1-SA to t-MCAO rats dramatically reduced brain damage caused by cerebral ischemia/reperfusion. These results establish that a statistical copolymer, selected from a small library of candidates synthesized using an “informed” selection of functional monomers, can yield a functional synthetic antibody. The knowledge gained from these experiments can facilitate the discovery, design, and development of a new category of drug.

更新日期：2023-10-16

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