The Combinatorial Design of Protein Molecular Switches

蛋白质分子开关的组合设计

• 批准号: 8641375
• 负责人: MARC A OSTERMEIER
• 金额: $ 35.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641375
• 关键词: Algorithm Design; Animal Model; Behavior; Biodistribution; Biological; Blood Circulation; Breast Cancer Cell; Bystander Effect; Cancer cell line; Cell Culture Techniques; Cell physiology; Cells; Colon Carcinoma; Complex; Coupling; Cytosine deaminase; Development; Disease; EP300 gene; Engineering; Enzymes; Escherichia coli; Evolution; Fluorouracil; Funding; Ganciclovir; Gene Fusion; Genes; Genetic Recombination; Goals; Human; Intravenous; Libraries; Ligands; Malignant Neoplasms; Measures; Methods; Molecular; Monitor; Mus; Output; Peptides; Phosphotransferases; Plasmids; Prodrugs; Property; Protein Engineering; Proteins; Regulation; Research; Signal Transduction; Simplexvirus; Surface; Switch Genes; Techniques; Testing; Therapeutic; Thymidine Kinase; Toxic effect; Virus; Xenograft Model; Xenograft procedure; Yeasts; Zidovudine; base; cancer cell; cancer therapy; combinatorial; design; directed evolution; enzyme activity; expression vector; genetic selection; hypoxia inducible factor 1; improved; in vivo; insight; killings; nanoparticle; nucleoside analog; penciclovir; protein function; public health relevance; screening; therapeutic protein; therapeutic target; therapy design; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Proteins that behave as switches hold great promise as selective protein therapeutics. Previous studies by the PI have demonstrated that protein switches can be engineered by creating a large number of different fusions between two genes and subjecting these gene fusions to evolution in the lab. Such directed evolution strategies will be used to develop and improve protein switches to effectively activate prodrugs selectively in cancer cells. These switches will be evaluated for their ability to eliminate tumor xenographs in vivo using endogenous expression and via systemic delivery. These switches in combination with the appropriate prodrug have potential as a targeted therapeutic for the treatment of cancer.

描述（由申请人提供）：作为开关的蛋白质作为选择性蛋白质治疗剂具有巨大的希望。 PI先前的研究表明，可以通过在两个基因之间创建大量不同的融合并将这些基因融合在实验室中进化来设计蛋白质开关。这种定向的进化策略将用于开发和改善蛋白质开关，以有效地在癌细胞中有效激活前药。这些开关将评估它们使用内源性表达和通过全身递送消除体内肿瘤Xenographss的能力。这些转换与适当的前药结合使用，具有针对癌症治疗的靶向治疗方法。