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J. Am. Chem. Soc., Sep 04 2023 | https://doi.org/10.1021/jacs.3c06898 Supramolecular Senolytics via Intracellular Oligomerization of Peptides in Response to Elevated Reactive Oxygen Species Levels in Aging Cells.

Sangpil Kim,^1# Jae-Byoung Chae,^2# Dohyun Kim,^1# Chul-Woo Park², Youjung Sim¹, Hyungwoo Lee², Gaeun Park¹, Jaeeun Lee¹, Seongho Hong¹, Batakrishna Jana¹, Chaekyu Kim³, Hyewon Chung,^2* and Ja-Hyoung Ryu^1*

¹Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.

²Department of Ophthalmology, Konkuk University School of Medicine, Seoul 05029, Republic of Korea.

³Fusion Biotechnology, Ulsan 44919, Republic of Korea.

^#S.K.,J.-B.C., and D.K. contributed equally.

^*Corresponding Authors : Hyewon Chung, Ja-Hyoung Ryu

Abstract

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 _vβ ₃-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 _vβ ₃, 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.

논문정보

형식Research article
게재일2023년 09월 (BRIC 등록일 2023-09-19)
연구진국내 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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