School of Pharmacy & Minhang Hospitol, Fudan University, Shanghai 201301, China.
Department of Biopharmaceuticals, School of Pharmacy, Fudan University, Shanghai 201301, China.
Eur J Med Chem. 2024 Sep 5;275:116581. doi: 10.1016/j.ejmech.2024.116581. Epub 2024 Jun 10.
Nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) constitutes an essential inflammasome sensor protein, pivotal in the orchestration of innate immunity. Given its paramount role, NLRP3 has recently emerged as an enticing therapeutic target for disorders associated with inflammation. In this study, we embarked on the design and synthesis of two series of compounds, endowed with the capacity to induce NLRP3 degradation via autophagy-tethering compounds (ATTECs)-an innovative targeted protein degradation technology. Notably, MC-ND-18 emerged as the most potent agent for effectuating NLRP3 degradation through autophagic mechanisms and concurrently exhibited marked anti-inflammatory efficacy in mice model of dextran sulfate sodium (DSS)-induced colitis. Consequently, we have successfully developed a pioneering NLRP3 protein degrader, offering a novel therapeutic avenue for ameliorating NLRP3-associated pathologies.
核苷酸结合寡聚化结构域样受体富含亮氨酸重复蛋白 3（NLRP3）构成了一种必不可少的炎症小体传感器蛋白，在先天免疫的协调中起着关键作用。鉴于其至关重要的作用，NLRP3 最近成为与炎症相关疾病的诱人治疗靶点。在这项研究中，我们着手设计和合成了两个系列的化合物，这些化合物具有通过自噬连接物（ATTECs）诱导 NLRP3 降解的能力——这是一种创新的靶向蛋白质降解技术。值得注意的是，MC-ND-18 是通过自噬机制实现 NLRP3 降解的最有效试剂，并且在葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型中表现出显著的抗炎功效。因此，我们成功开发了一种开创性的 NLRP3 蛋白降解剂，为改善 NLRP3 相关病理提供了一种新的治疗途径。
