Department of Chemical Engineering, Stanford University, Stanford, California 94305, United States.
Department of Chemistry, Stanford University, Stanford, California 94305, United States.
J Am Chem Soc. 2023 Aug 30;145(34):18705-18710. doi: 10.1021/jacs.3c05109. Epub 2023 Aug 17.
Protein dysregulation has been characterized as the cause of pathogenesis in many different diseases. For proteins lacking easily druggable pockets or catalytically active sites, targeted protein degradation is an attractive therapeutic approach. While several methods for targeted protein degradation have been developed, there remains a demand for lower molecular weight molecules that promote efficient degradation of their targets. In this work, we describe the synthesis and validation of a series of heterobifunctional molecules that bind a protein of interest through a small molecule ligand while targeting them to the lysosome using a short gluten peptide that leverages the TG2/LRP-1 pathway. We demonstrate that this approach can be used to effectively endocytose and degrade representative secreted, cell surface, and transmembrane proteins, notably streptavidin, the vitamin B12 receptor, cubilin, and integrin αβ. Optimization of these prototypical molecules could generate pharmacologically relevant LYTAC agents.
蛋白质失调已被确定为许多不同疾病发病机制的原因。对于缺乏易于成药口袋或催化活性位点的蛋白质，靶向蛋白质降解是一种有吸引力的治疗方法。虽然已经开发了几种靶向蛋白质降解的方法，但仍需要能够促进其靶标有效降解的低分子量分子。在这项工作中，我们描述了一系列杂双功能分子的合成和验证，这些分子通过小分子配体与感兴趣的蛋白质结合，同时利用利用 TG2/LRP-1 途径的短谷氨酰胺肽将其靶向溶酶体。我们证明，这种方法可用于有效内化和降解代表性的分泌型、细胞表面和跨膜蛋白，特别是链霉亲和素、维生素 B12 受体、内因子和整合素 αβ。这些原型分子的优化可以产生具有药理相关性的 LYTAC 药物。
