Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy. Most TPD technologies use the ubiquitin–proteasome system, and are therefore limited to targeting intracellular proteins. To address this limitation, we developed a class of modular, bifunctional synthetic molecules called MoDE-As (molecular degraders of extracellular proteins through the asialoglycoprotein receptor (ASGPR)), which mediate the degradation of extracellular proteins. MoDE-A molecules mediate the formation of a ternary complex between a target protein and ASGPR on hepatocytes. The target protein is then endocytosed and degraded by lysosomal proteases. We demonstrated the modularity of the MoDE-A technology by synthesizing molecules that induce depletion of both antibody and proinflammatory cytokine proteins. These data show experimental evidence that nonproteinogenic, synthetic molecules can enable TPD of extracellular proteins in vitro and in vivo. We believe that TPD mediated by the MoDE-A technology will have widespread applications for disease treatment.

靶向蛋白质降解（TPD）已成为一种有前途的治疗策略。大多数 TPD 技术使用泛素-蛋白酶体系统，因此仅限于靶向细胞内蛋白质。为了解决这一限制，我们开发了一类模块化的双功能合成分子，称为 MoDE-As（通过去唾液酸糖蛋白受体 (ASGPR) 降解细胞外蛋白的分子降解剂），它介导细胞外蛋白的降解。MoDE-A分子介导靶蛋白和肝细胞上的ASGPR之间形成三元复合物。然后靶蛋白被溶酶体蛋白酶内吞和降解。我们通过合成诱导抗体和促炎细胞因子蛋白消耗的分子证明了 MoDE-A 技术的模块化。这些数据显示了非蛋白合成分子可以在体外和体内实现细胞外蛋白的 TPD 的实验证据。我们相信由MoDE-A技术介导的TPD将在疾病治疗中具有广泛的应用。