Mesfin Joshua M, Carrow Kendal P, Chen Alexander, Hopps Madeline P, Holm JoJo J, Lyons Quincy P, Nguyen Michael B, Hunter Jervaughn D, Magassa Assa, Wong Elyse G, Reimold Kate, Paleti Sriya N, Gardner Emily, Thompson Matthew P, Luo Colin G, Zhang Xiaoyu, Christman Karen L, Gianneschi Nathan C
Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, 92037, USA.
Medical Scientist Training Program, Department of Biomedical Engineering, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Adv Mater. 2025 Jul;37(27):e2417885. doi: 10.1002/adma.202417885. Epub 2025 Apr 25.
Myocardial infarction (MI) results in oxidative stress to the myocardium and frequently leads to heart failure (HF). There is an unmet clinical need to develop therapeutics that address the inflammatory stress response and prevent negative left ventricular remodeling. Here, the Keap1/Nrf2 protein-protein interaction is specifically targeted, as Nrf2 activation is known to mitigate the inflammatory response following MI. This is achieved using a Nrf2-mimetic protein-like polymer (PLP) to inhibit the Keap1-Nrf2 interaction. The PLP platform technology provides stability in vivo, potent intracellular bioactivity, and multivalency leading to high avidity Keap1 binding. In vitro and in vivo assays to probe cellular activity and MI therapeutic utility are employed. These Keap1-inhibiting PLPs (Keap1i-PLPs) impart cytoprotection from oxidative stress via Nrf2 activation at sub-nanomolar concentrations in primary cardiomyocytes. Single-digit mg kg, single-dose, intravenous PLP administration significantly improves cardiac function in rats post-MI through immunomodulatory, anti-apoptotic, and angiogenic mechanisms. Thus Keap1i-PLPs disrupt key intracellular protein-protein interactions following intravenous, systemic administration in vivo. These results have broad implications not only for MI but also for other oxidative stress-driven diseases and conditions.
心肌梗死（MI）会导致心肌氧化应激，并常常引发心力衰竭（HF）。开发能够应对炎症应激反应并预防左心室负性重构的治疗方法，这一临床需求尚未得到满足。在此，特异性靶向Keap1/Nrf2蛋白-蛋白相互作用，因为已知Nrf2激活可减轻心肌梗死后的炎症反应。这是通过使用一种模拟Nrf2的蛋白样聚合物（PLP）来抑制Keap1-Nrf2相互作用实现的。PLP平台技术在体内具有稳定性、强大的细胞内生物活性以及多价性，从而导致对Keap1的高亲和力结合。采用体外和体内试验来探究细胞活性和心肌梗死治疗效用。这些抑制Keap1的PLP（Keap1i-PLPs）在原代心肌细胞中以亚纳摩尔浓度通过激活Nrf2赋予细胞对氧化应激的保护作用。以个位数毫克/千克的单剂量静脉注射PLP，通过免疫调节、抗凋亡和血管生成机制，可显著改善心肌梗死后大鼠的心脏功能。因此，Keap1i-PLPs在体内静脉全身给药后会破坏关键的细胞内蛋白-蛋白相互作用。这些结果不仅对心肌梗死，而且对其他氧化应激驱动的疾病和病症都具有广泛的意义。
