通过肽的细胞内寡聚化来响应老化细胞中活性氧水平升高的超分子 Senolytics,Journal of the American Chemical Society

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通过肽的细胞内寡聚化来响应老化细胞中活性氧水平升高的超分子 Senolytics
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-09-04 , DOI: 10.1021/jacs.3c06898
Sangpil Kim ₁ , Jae-Byoung Chae ₂ , Dohyun Kim ₁ , Chul-Woo Park ₂ , Youjung Sim ₁ , Hyungwoo Lee ₂ , Gaeun Park ₁ , Jaeeun Lee ₁ , Seongho Hong ₁ , Batakrishna Jana ₁ , Chaekyu Kim ₃ , Hyewon Chung ₂ , Ja-Hyoung Ryu ₁

Affiliation

Senolytics 可以消除组织中的衰老细胞，代表了一种针对各种与年龄相关的疾病的新兴治疗策略。大多数 senolytics 都针对抗凋亡蛋白，这些蛋白在衰老细胞中过度表达，限制了特异性并引发严重的副作用。为了克服这些限制，我们构建了具有细胞内寡聚系统的针对衰老细胞的自组装 senolytics。细胞内含芳基二硫醇的肽寡聚化仅发生在衰老细胞的线粒体内，这是由于 RGD 介导的细胞摄取将肽选择性定位到整合素 α v β 3 过表达的_衰老细胞_中以及活性氧水平升高，这可能是由于用作二硫化物形成的化学燃料。这种寡聚化产生具有稳定的α螺旋二级结构的人工蛋白质样纳米组装体，它可以通过多价相互作用破坏线粒体膜，因为衰老细胞的线粒体膜的完整性比正常细胞的完整性更弱。衰老细胞的这三种特性（整合素 α _v β ₃、高 ROS 和弱线粒体膜完整性）结合在一起发挥作用；因此，这种线粒体内寡聚化系统可以选择性诱导衰老细胞凋亡，而不会对正常细胞产生副作用。在年龄相关性黄斑变性小鼠模型和老年小鼠中，通过这种肽senolytic消除衰老的视网膜色素上皮后，观察到关键衰老标志物显着减少并改善视网膜变性，并且这种效果伴随着视觉功能的改善。该系统提供了使用超分子衰老剂治疗与年龄相关的疾病的策略。

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Supramolecular Senolytics via Intracellular Oligomerization of Peptides in Response to Elevated Reactive Oxygen Species Levels in Aging Cells

Senolytics, which eliminate senescent cells from tissues, represent an emerging therapeutic strategy for various age-related diseases. Most senolytics target antiapoptotic proteins, which are overexpressed in senescent cells, limiting specificity and inducing severe side effects. To overcome these limitations, we constructed self-assembling senolytics targeting senescent cells with an intracellular oligomerization system. Intracellular aryl-dithiol-containing peptide oligomerization occurred only inside the mitochondria of senescent cells due to selective localization of the peptides by RGD-mediated cellular uptake into integrin α_vβ₃-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin α_vβ₃, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells. Significant reductions in key senescence markers and amelioration of retinal degeneration were observed after elimination of the senescent retinal pigment epithelium by this peptide senolytic in an age-related macular degeneration mouse model and in aged mice, and this effect was accompanied by improved visual function. This system provides a strategy for the treatment of age-related diseases using supramolecular senolytics.

更新日期：2023-09-04

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