Hydrocarbon-stapled polypeptides for enhancement of endosome-lysosomal degradation

Abstract

The present invention relates to a Beclin1-UVRAG complex structure which reveals a tightly packed coiled coil assembly with Beclin 1 and UVRAG residues complementing each other to form a stable dimeric complex. This potent physical interaction is critical for UVRAG-dependent EGFR degradation but less critical for autophagy. Targeting the Beclin coiled coil domain with rationally designed stapled peptides leads to enhanced autophagy activity and EGFR degradation in non-small cell lung cancer (NSCLC) cell lines, suggesting translational value for these compounds. 本发明涉及一种Beclin1‑UVRAG复合体结构，而Beclin1和UVRAG卷曲螺旋形组件的残基紧密互补形成稳定的二聚体复合物。这种有效的物理相互作用对于依赖UVRAG的EGFR降解是关键的，但不影响自噬。针对Beclin1卷曲螺旋形结构域而设计的订装肽可导致非小细胞肺癌(NSCLC)细胞系增强自噬活性和EGFR降解，显示这些化合物的价值。