Development of Protein Like Polymer Therapeutics for Modulating the Nrf2/Keap1 Protein Protein Interaction in Neurodegenerative Diseases

开发用于调节神经退行性疾病中 Nrf2/Keap1 蛋白相互作用的类蛋白聚合物疗法

• 批准号: 10537489
• 负责人: Kendal Paige Carrow
• 金额: $ 5.1万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-09-10
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537489
• 关键词: Address; Affinity; Age; Aging; Alzheimer' s Disease; Antioxidants; Attention; Automobile Driving; Autophagocytosis; Binding; Binding Sites; Biogenesis; Biological; Biological Assay; Biomimetics; Cells; Central Nervous System Diseases; Chemicals; Chemistry; Chimera organism; Clinical; Clinical Skills; Development; Drug Kinetics; Drug Targeting; Equipment; Erythroid; Evaluation; Excision; Exhibits; Flow Cytometry; Fostering; Half-Life; HepG2; Homeostasis; Hydrophobicity; In Vitro; Inflammation; Length; Mitochondria; Modeling; Molecular Weight; Morbidity - disease rate; Morphology; Mus; NF-E2-related factor 2; Nerve Degeneration; Neuraxis; Neurobiology; Neurodegenerative Disorders; Nuclear; Outcome; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Penetration; Peptides; Performance; Permeability; Pharmaceutical Preparations; Physicians; Play; Polymers; Preparation; Property; Proteins; Proteolysis; Reporter; Research; Research Personnel; Resistance; Response Elements; Role; Scientist; Specificity; Stress; Structure; System; Technical Expertise; Therapeutic; Toxic effect; Training; Transgenic Organisms; Universities; Western Blotting; Wisconsin; Work; age related; base; biomaterial compatibility; career; clinical translation; clinically translatable; copolymer; density; design; dimer; hemocompatibility; immunogenicity; improved; in silico; in vivo; inhibitor; insight; interest; materials science; mimetics; mortality; novel; novel therapeutics; peptide drug; polymerization; protein aminoacid sequence; protein degradation; protein protein interaction; response; sensor; small molecule; targeted treatment; therapeutic target; tool; transcription factor; translational therapeutics; uptake

PROJECT SUMMARY There is significant interest in developing therapeutics targeting the protein-protein interaction between nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and kelch-like ECH-associating protein 1 (Keap1) for neurodegenerative disease. A therapeutic that successfully and selectively inhibits Keap1/Nrf2 binding would enhance the cellular antioxidant response leading to a neuroprotective effect. Such inhibition of the Keap1/Nrf2 interaction could revolutionize our ability to treat multiple neurodegenerative diseases such as Alzheimer’s Disease. Inhibitory peptide therapeutics are of increasing interest but are limited in their pharmacokinetic profiles, cellular penetration, and efficacy. The proposed approach overcomes these challenges utilizing high-density brush polymer structures that are capable of engaging Keap1 and displacing the cellular protective transcription factor, Nrf2. These unique structures, termed protein-like polymers (PLPs), display specific Nrf2-derived peptide sequences around a hydrophobic synthetic polymer core. Compared to peptides alone, PLPs demonstrate resistance to proteolysis, improved pharmacokinetics, bioactivity and efficient cellular uptake. The PLP platform is proposed here for the development of two novel types of Keap1-inhibitors that overcome the current challenges limiting Keap1/Nrf2 targeted therapeutics. Keap1-targeting PLPs are the focus here due to the documented neuroprotective role of Nrf2 and the large unmet clinical need in neurodegenerative disease broadly. A key focus will be on the development of PLPs to competitively inhibit Keap1 and subsequently establish their efficacy as Nrf2 activators. Peptides identified via in silico modeling will be incorporated into PLPs and then evaluated by in vitro and in vivo analysis to determine bioactivity and pharmacokinetic properties. PLPs can be prepared with morphologies and molecular weights similar to proteins. Therefore, we will explore the effects of varying molecular weight, and thus polymer length, on Keap1-inhibition and bioactivity. In addition, PLPs can be prepared with multiple peptide-based domains. This multifunctionality combined with multivalency will be used to develop Nrf2 mimetics capable of spanning and selectively binding both Keap1 binding sites. Finally, the PLP platform will be used to design a class of Keap1-inhibitors capable of heterobifunctional binding, enabling targeted degradation of Keap1. These PLPs, designed as autophagy targeting chimeras (AUTACs), will selectively target Keap1 and shuttle the protein for degradation through the autophagy pathway. The proposed research plan seeks to address the current gaps facing translational therapeutics targeting the Keap1/Nrf2 interaction. The proposed research will be conducted under the guidance of Dr. Nathan Gianneschi and Dr. Jeffrey Johnson to establish technical skills in both materials science/chemistry and neurobiology respectively and with access to expertise and equipment at Northwestern University and the University of Wisconsin. The proposed training plan will develop the applicant into an independent researcher and foster clinical skills in preparation for a career as a physician scientist developing novel therapeutic platforms.

项目概要 人们对开发针对核之间蛋白质-蛋白质相互作用的治疗方法非常感兴趣。 因子（红细胞衍生 2）样 2 (Nrf2) 和 kelch 样 ECH 相关蛋白 1 (Keap1) 用于治疗神经退行性疾病 成功且选择性地抑制 Keap1/Nrf2 结合的治疗方法将增强细胞的功能。 Keap1/Nrf2 相互作用的这种抑制可能会导致抗氧化反应。 彻底改变我们治疗阿尔茨海默病等多种神经退行性疾病的能力。 肽疗法越来越受到人们的关注，但其药代动力学特征、细胞 所提出的方法利用高密度刷子克服了这些挑战。 能够接合 Keap1 并取代细胞保护性转录因子的聚合物结构， Nrf2。这些独特的结构被称为类蛋白聚合物 (PLP)，显示出特定的 Nrf2 衍生肽。 与单独的肽相比，PLP 证明了疏水性合成聚合物核心周围的序列。 抗蛋白水解、改善药代动力学、生物活性和有效的细胞摄取。 这里建议开发两种新型 Keap1 抑制剂来克服当前的挑战 由于有文献记载，限制 Keap1/Nrf2 靶向治疗是这里的焦点。 Nrf2 的神经保护作用以及神经退行性疾病中大量未满足的临床需求。 重点将放在开发 PLP 以竞争性抑制 Keap1 并随后建立 通过计算机模型鉴定出它们作为 Nrf2 激活剂的功效，然后将其纳入 PLP 中。 通过体外和体内分析进行评估，以确定 PLP 的生物活性和药代动力学特性。 其形态和分子量与蛋白质相似，因此，我们将探讨其效果。 此外，PLP 的分子量和聚合物长度也会对 Keap1 抑制和生物活性产生影响。 将使用由多个基于肽的结构域制备的多功能性与多价性。 开发能够跨越并选择性结合两个 Keap1 结合位点的 Nrf2 模拟物。 该平台将用于设计一类能够异双功能结合的 Keap1 抑制剂，从而使 这些 PLP 被设计为自噬靶向嵌合体 (AUTAC)，将被靶向降解。 选择性地靶向 Keap1 并穿梭蛋白质通过自噬途径进行降解。 拟议的研究计划旨在解决目前转化疗法靶向面临的差距 Keap1/Nrf2 相互作用。拟议的研究将在 Nathan 博士的指导下进行。 Gianneschi 和 Jeffrey Johnson 博士将建立材料科学/化学和 分别拥有西北大学和神经生物学的专业知识和设备 威斯康星大学拟议的培训计划将把申请人培养成一名独立研究员。 培养临床技能，为开发新型治疗平台的医师科学家的职业生涯做好准备。