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.

项目摘要 对靶向核蛋白质蛋白相互作用的治疗产生了重大兴趣 因子（红细胞衍生的2）类似于2（NRF2）和类似Kelch的ECH缔解蛋白1（KEAP1）用于神经退行性的蛋白1（KEAP1） 疾病。成功和选择性地抑制KEAP1/NRF2结合的疗法将增强细胞 抗氧化剂反应导致神经保护作用。这种抑制KEAP1/NRF2相互作用可以 彻底改变了我们治疗多种神经退行性疾病（例如阿尔茨海默氏病）的能力。抑制性 肽疗法的兴趣增加，但在其药代动力学特征，细胞中受到限制 渗透和效率。提出的方法克服了利用高密度刷的这些挑战 能够吸引KEAP1并取代细胞受保护转录因子的聚合物结构， NRF2。这些独特的结构，称为蛋白质样聚合物（PLP），显示特定的NRF2衍生肽 疏水合成聚合物核周围的序列。与仅辣椒相比，PLP证明 对蛋白水解的抗性，改善的药代动力学，生物活性和有效的细胞摄取。 PLP平台 这里提出了开发两种新型的KEAP1抑制剂，以克服当前的挑战 限制KEAP1/NRF2靶向治疗。由于已记录的 NRF2的神经保护作用以及广泛的神经退行性疾病中的巨大未满足临床需求。 重点将是PLP的开发，以竞争性抑制KEAP1并随后建立 它们作为NRF2激活剂的效率。通过计算机建模中鉴定的肽将掺入PLP中，然后将 通过体外和体内分析评估以确定生物活性和药代动力学特性。 PLP可以 用形态学和类似于蛋白质的分子量制备。因此，我们将探讨 在KEAP1抑制和生物活性方面，分子量变化，因此聚合物长度。另外，PLP可以是 用多个基于肽的域制备。将使用这种多功能性与多函数相结合 为了开发能够跨越和选择性结合两个KEAP1结合位点的NRF2 Mimetics。最后，PLP 平台将用于设计能够异常结合的KEAP1抑制剂 KEAP1的靶向降解。这些PLP设计为自噬靶向嵌合体（AUTACS），将 选择性地靶向Keap1并穿梭蛋白质以通过自噬途径降解。 拟议的研究计划旨在解决翻译疗法靶向的当前差距 KEAP1/NRF2相互作用。拟议的研究将在内森博士的指导下进行 Gianneschi和Jeffrey Johnson博士在材料科学/化学和 神经生物学分别以及西北大学获得专业知识和设备的机会 威斯康星大学。拟议的培训计划将把申请人发展为独立研究人员 并培养临床技能，为发展新型治疗平台的物理科学家做好准备。