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:
- 金额:$ 39.42万
- 依托单位:
- 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:
- 关键词:AffectAffinityAmino AcidsAntibodiesAntineoplastic AgentsBindingBinding ProteinsBiological Response Modifier TherapyCancer cell lineCell physiologyCell surfaceCellsDataDevelopmentDiagnosticDimensionsDiseaseERBB2 geneGenerationsGeneticHumanImmuneImmune checkpoint inhibitorIn VitroLeadLigandsMalignant NeoplasmsMeasuresMembraneMethodsPharmaceutical PreparationsPropertyProteinsReceptor CellResearchResearch PersonnelSideSignal TransductionT-Cell ActivationTechnologyTherapeuticTranslatingXenograft procedureanticancer researchcancer cellcancer therapycheckpoint receptorscovalent bondcytotoxiccytotoxicitydesignimmune checkpointin vivoinnovationmouse modelnanobodiesnovelprotein protein interactionreactivation from latencyreceptorreconstitutionsmall moleculesuccesstherapeutic proteintumortumor growthtumor xenograftunnatural 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递。各种蛋白质结合剂
已经被开发来检测或调节这种相互作用以用于研究、诊断和治疗
申请。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,
对亲和力、稳定性和完整性的限制。此外,药物与其靶标之间的共价键
与传统药物的非共价相互作用相比,提供了多种理想的治疗特性。是这样的
近年来,共价模式在小分子药物中的应用取得了很大的成功,但
共价蛋白质药物的治疗潜力在很大程度上仍未开发。为了改变这种模式,这个项目
将开发共价蛋白质结合剂并生产共价蛋白质药物。新的潜在生物活性氨基酸
将被设计并通过基因结合到蛋白质结合剂中,它将与天然残留物发生反应
仅靶向于蛋白质结合,选择性地在两种蛋白质之间建立稳定的共价键。
与癌症相关的免疫检查点和膜受体的共价蛋白结合蛋白将
将被生成。这些共价蛋白结合剂对癌细胞信号和功能的不同影响将是
在体外进行评估,并将评估它们作为共价蛋白药物的细胞毒活性和抗肿瘤效果。
在异种移植小鼠模型中。该项目的成功将为细胞研究开辟一个新的领域
通过高度选择性、稳定和共价调节蛋白质的信号和功能。一个通用的平台
将建立开发共价蛋白质药物的技术,导致新一代
具有根本不同的癌症治疗结合机制的生物疗法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lei Wang其他文献
Palladium-Catalyzed ortho-Acylation of Acetanilides with Aldehydes via Direct CH Bond Activation.
通过直接 C·H 键活化,钯催化乙酰苯胺与醛的邻位酰化。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Chengliang Li;Lei Wang;Pinhua Li;Wei Zhou - 通讯作者:
Wei Zhou
KOAc-promoted alkynylation of alpha-C-H bonds of ethers with alkynyl bromides under transition-metal-free conditions
无过渡金属条件下 KOAc 促进醚的 α-C-H 键与炔基溴的炔基化
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:3.2
- 作者:
Jiajun Zhang;Pinhua Li;Lei Wang - 通讯作者:
Lei Wang
Lei Wang的其他文献
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{{ truncateString('Lei Wang', 18)}}的其他基金
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
- 批准号:
10179199 - 财政年份:2021
- 资助金额:
$ 39.42万 - 项目类别:
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
- 批准号:
10569518 - 财政年份:2021
- 资助金额:
$ 39.42万 - 项目类别:
TERBO BRAIN Study: Trajectories of Emotional Regulation and Behavior Outcomes and related Brain Regions And Intrinsic Networks
TERBO BRAIN 研究:情绪调节和行为结果的轨迹以及相关的大脑区域和内在网络
- 批准号:
10065446 - 财政年份:2020
- 资助金额:
$ 39.42万 - 项目类别:
Schwann cell derived exosomes improve diabetic peripheral neuropathy in type II diabetic mice
雪旺细胞衍生的外泌体改善 II 型糖尿病小鼠的糖尿病周围神经病变
- 批准号:
10121320 - 财政年份:2020
- 资助金额:
$ 39.42万 - 项目类别:
TERBO BRAIN Study: Trajectories of Emotional Regulation and Behavior Outcomes and related Brain Regions And Intrinsic Networks
TERBO BRAIN 研究:情绪调节和行为结果的轨迹以及相关的大脑区域和内在网络
- 批准号:
10663934 - 财政年份:2020
- 资助金额:
$ 39.42万 - 项目类别:
TERBO BRAIN Study: Trajectories of Emotional Regulation and Behavior Outcomes and related Brain Regions And Intrinsic Networks
TERBO BRAIN 研究:情绪调节和行为结果的轨迹以及相关的大脑区域和内在网络
- 批准号:
10264955 - 财政年份:2020
- 资助金额:
$ 39.42万 - 项目类别:
Schwann cell derived exosomes improve diabetic peripheral neuropathy in type II diabetic mice
雪旺细胞衍生的外泌体改善 II 型糖尿病小鼠的糖尿病周围神经病变
- 批准号:
10413254 - 财政年份:2020
- 资助金额:
$ 39.42万 - 项目类别:
Schwann cell derived exosomes improve diabetic peripheral neuropathy in type II diabetic mice
雪旺细胞衍生的外泌体改善 II 型糖尿病小鼠的糖尿病周围神经病变
- 批准号:
10643939 - 财政年份:2020
- 资助金额:
$ 39.42万 - 项目类别:
Schwann cell derived exosomes improve diabetic peripheral neuropathy in type II diabetic mice
雪旺细胞衍生的外泌体改善 II 型糖尿病小鼠的糖尿病周围神经病变
- 批准号:
10262969 - 财政年份:2020
- 资助金额:
$ 39.42万 - 项目类别:
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10609888 - 财政年份:2020
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