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

• DOI: 10.1021/jacs.3c06898
• Publication Date: 2023-09-04T09:34:40Z
• Authors: Sangpil Kim; Jae-Byoung Chae; Dohyun Kim; Chul-Woo Park; Youjung Sim; Hyungwoo Lee; Gaeun Park; Jaeeun Lee; Seongho Hong; Batakrishna Jana; Chaekyu Kim; Hyewon Chung; Ja-Hyoung Ryu
• Keywords: Mice; Integrins; Senotherapeutics; 610; Animals; Reactive Oxygen Species; Peptides; Cellular Senescence; 3. Good health

Senolytics, which eliminate senescent cells from tissues, represent an emerging therapeutic strategy for various age-related diseases. Most senolytics target antiapoptotic proteins, are overexpressed in cells, limiting specificity and inducing severe side effects. To overcome these limitations, we constructed self-assembling targeting with intracellular oligomerization system. Intracellular aryl-dithiol-containing peptide occurred only inside the mitochondria of due to selective localization peptides by RGD-mediated cellular uptake into integrin αvβ3-overexpressed elevated levels reactive oxygen species, can be used as a chemical fuel disulfide formation. This results artificial protein-like nanoassembly stable α-helix secondary structure, disrupt mitochondrial membrane via multivalent interactions because has weaker integrity than that normal cells. These three specificities (integrin αvβ3, high ROS, weak integrity) work combination; therefore, this intramitochondrial system selectively induce apoptosis without effects on Significant reductions key senescence markers amelioration retinal degeneration were observed after elimination pigment epithelium senolytic macular mouse model aged mice, effect was accompanied improved visual function. provides treatment diseases using supramolecular senolytics.