Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by aggregation of mutant huntingtin (mHtt), and removal of mHtt is expected as a potential therapeutic option. We previously reported protein knockdown of Htt by using hybrid small molecules (Htt degraders) consisting of BE04, a ligand of ubiquitin ligase (E3), linked to probes for protein aggregates. Here, in order to examine the effect of changing the ligand, we synthesized a similar Htt degrader utilizing MV1, an antagonist of the inhibitor of apoptosis protein (IAP) family (a subgroup of ubiquitin E3 ligases), which is expected to have a higher affinity and specificity for IAP, as compared with BE04. The MV1-based hybrid successfully induced interaction between Htt aggregates and IAP, and reduced mHtt levels in living cells. Its mode of action was confirmed to be the same as that of the BE04-based hybrid. However, although the affinity of MV1 for IAP is greater than that of BE04, the efficacy of Htt degradation by the MV1-based molecule was lower, suggesting that linker length between the ligand and probe might be an important determinant of efficacy.

亨廷顿舞蹈病（HD）是由突变亨廷顿蛋白（mHtt）聚集引起的常染色体显性遗传神经退行性疾病，预计将mHtt去除是一种潜在的治疗选择。我们先前报道了通过使用由BE04（一种泛素连接酶（E3）的配体）组成的杂合小分子（Htt降解物）与Htt进行蛋白敲除的方法，该杂合子与蛋白质聚集体的探针连接。在这里，为了检查改变配体的作用，我们利用MV1（凋亡蛋白（IAP）家族（泛素E3连接酶的一个亚类）抑制剂）的拮抗剂MV1合成了类似的Htt降解体。与BE04相比，对IAP的亲和力和特异性更高。基于MV1的杂种成功诱导Htt聚集体和IAP之间的相互作用，并降低了活细胞中的mHtt水平。确认其作用方式与基于BE04的混合动力车相同。但是，尽管MV1对IAP的亲和力大于BE04，但基于MV1的分子对Htt降解的功效较低，这表明配体与探针之间的接头长度可能是功效的重要决定因素。