Covalent Protein Binders for Cancer Research and Therapy

用于癌症研究和治疗的共价蛋白结合剂

基本信息

批准号：
10360531
负责人：
Lei Wang
金额：
$ 39.42万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360531
关键词：
Affect Affinity Amino Acids Antibodies Antineoplastic Agents Binding Binding Proteins Biological Response Modifier Therapy Cancer cell line Cell physiology Cell surface Cells Data Development Diagnostic Dimensions Disease ERBB2 gene Generations Genetic Human Immune Immune checkpoint inhibitor In Vitro Lead Ligands Malignant Neoplasms Measures Membrane Methods Pharmaceutical Preparations Property Proteins Receptor Cell Research Research Personnel Side Signal Transduction T-Cell Activation Technology Therapeutic Translating Xenograft procedure anticancer research cancer cell cancer therapy checkpoint receptors covalent bond cytotoxic cytotoxicity design immune checkpoint in vivo innovation mouse model nanobodies novel protein protein interaction reactivation from latency receptor reconstitution small molecule success therapeutic protein tumor tumor growth tumor xenograft unnatural amino acids

项目摘要

Protein-protein interactions are involved in a broad range of cell function and signaling. Various protein binders have been developed to detect or modulate such interactions for research, diagnostic, and therapeutic applications. However, existing protein binders usually bind to their targets in noncovalent mode only, imposing limitations on affinity, stability, and completeness. In addition, covalent bonding between a drug and its target offers multiple desirable therapeutic properties over noncovalent interactions of conventional drugs. Such covalent mode has been implemented in small molecule drugs with great success in recent years, yet the therapeutic potential of covalent protein drugs remains largely untapped. To change this paradigm, this project will develop covalent protein binders and generate covalent protein drugs. New latent bioreactive amino acids will be designed and genetically incorporated into protein binders, which will react with a natural residue of the target only upon protein binding, selectively creating a stable covalent linkage between the two proteins. Covalent protein binders specific for immune-checkpoints and membrane receptors associated with cancer will be generated. The distinct effects of these covalent protein binders on cancer cell signaling and function will be assessed in vitro, and their cytotoxic activity and anti-tumor efficacy as covalent protein drugs will be evaluated in xenografted mouse models. The success of this project will instigate a new dimension for researching cell signaling and function through highly selective, stable, and covalent modulation of proteins. A general platform technology will be established for the development of covalent protein drugs, leading to a new generation of biotherapeutics with a fundamentally different binding mechanism for cancer treatment.

蛋白质-蛋白质相互作用涉及广泛的细胞功能和信号传导。各种蛋白质结合剂已被开发用于检测或调节这种相互作用以用于研究、诊断和治疗应用程序。然而，现有的蛋白质结合剂通常仅以非共价模式与其靶标结合，这使得亲和力、稳定性和完整性方面的限制。此外，药物与其靶标之间存在共价键合与传统药物的非共价相互作用相比，具有多种理想的治疗特性。这样的近年来，共价模式在小分子药物中的应用取得了巨大成功，但共价蛋白药物的治疗潜力在很大程度上尚未开发。为了改变这种范式，这个项目将开发共价蛋白结合剂并生成共价蛋白药物。新的潜在生物活性氨基酸将被设计并通过基因整合到蛋白质结合剂中，该结合剂将与蛋白质的天然残留物发生反应仅针对蛋白质结合，选择性地在两种蛋白质之间建立稳定的共价连接。与癌症相关的免疫检查点和膜受体特异的共价蛋白结合剂将被生成。这些共价蛋白结合剂对癌细胞信号传导和功能的独特影响将是体外评估，将评估其作为共价蛋白药物的细胞毒活性和抗肿瘤功效在异种移植小鼠模型中。该项目的成功将为细胞研究开辟新的维度通过对蛋白质进行高度选择性、稳定和共价调节来发挥信号传导和功能。通用平台将建立用于开发共价蛋白药物的技术，从而产生新一代具有根本不同的癌症治疗结合机制的生物治疗药物。