Identification, validation and functional characterization of targets of myxobacterial compounds with potential for pharmacological cancer treatment
具有药物癌症治疗潜力的粘细菌化合物靶标的鉴定、验证和功能表征
基本信息
- 批准号:187769183
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Units
- 财政年份:2010
- 资助国家:德国
- 起止时间:2009-12-31 至 2013-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
This project focuses on target identification and validation via chemical proteomic based methods. In the first funding period we utilized functionalized pretubulysin derivatives for target analysis. While activity based protein profiling (ABPP) with cell permeable photoprobes revealed tubulin as target protein, affinity chromatography with immobilized pretubulisin provided evidence for the specific binding to proteasomal subunits. Especially the latter finding was unexpected and will be further validated during the next funding period. In the new funding period we will use our established chemical proteomic platform for the target characterization of soraphen A and archazolid. The design of both functionalized molecules will be carried out in close collaboration with P2 and P9. In order to gain quantitative data we will use stable isotope labeling in cell culture (SILAC). This method will allow to immediately rank the identified protein hits according to their binding specificity and thus increase the confidence in the obtained results. In addition, we will further refine the method of ABPP and implement a photolinker free native enrichment strategy that would allow to reduce the extent of structural modifications on the target compound. All novel hits will be validated by in depth biological characterization. Putative targets for archazolid have been predicted based on computational and biochemical data and will be also validated within these studies. With this comprehensive target identification/validation strategy we will provide important insights into the mechanism of action of the FOR compounds and thus help to generate hypotheses on the biological activity and mode of action.
该项目的重点是通过基于化学蛋白质组学的方法进行目标识别和验证。在第一个资助期,我们利用功能化的pretubulysin衍生物进行靶标分析。虽然基于活性的蛋白质分析(ABPP)与细胞可渗透的光探针显示微管蛋白作为靶蛋白,亲和层析与固定化pretubulisin提供了证据的特异性结合蛋白酶体亚基。特别是后一项发现是出乎意料的,将在下一个供资期内进一步验证。在新的资助期内,我们将使用我们建立的化学蛋白质组学平台对soraphen A和archazolid进行靶向表征。两种功能化分子的设计将与P2和P9密切合作进行。为了获得定量数据,我们将在细胞培养中使用稳定同位素标记(SILAC)。该方法将允许根据其结合特异性立即对鉴定的蛋白质命中进行排序,从而增加所获得结果的置信度。此外,我们将进一步完善ABPP的方法,并实施无光连接剂的天然富集策略,以减少目标化合物的结构修饰程度。将通过深入生物学表征对所有新命中进行验证。根据计算和生化数据预测了archazolid的假定靶点,并将在这些研究中进行验证。通过这种全面的目标识别/验证策略,我们将为FOR化合物的作用机制提供重要的见解,从而有助于产生关于生物活性和作用模式的假设。
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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Professor Dr. Stephan A. Sieber其他文献
Professor Dr. Stephan A. Sieber的其他文献
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{{ truncateString('Professor Dr. Stephan A. Sieber', 18)}}的其他基金
Exploiting quorum sensing inhibition of the natural products fimbrolide and elegaphenone in gram-negative bacteria
利用群体感应抑制革兰氏阴性菌中的天然产物芬溴内酯和榄香酮
- 批准号:
358921956 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Research Grants
Chemical-proteomic tools to monitor pyridoxal phosphorylation and its function as an enzyme cofactor in disease-related pathways
用于监测吡哆醛磷酸化及其作为疾病相关途径中酶辅因子的功能的化学蛋白质组学工具
- 批准号:
314976069 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Research Grants
Identification of chemical compounds to inhibit the caseinolytic protease ClpXP complex and evaluate their biological activity
抑制酪蛋白分解酶 ClpXP 复合物的化合物的鉴定并评估其生物活性
- 批准号:
282324388 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Research Grants
Protein targets of rugulactone and illudin S: An analysis of their function and mechanism of action
胡古内酯和隐球菌素 S 的蛋白质靶点:功能和作用机制分析
- 批准号:
233925483 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Research Grants
A chemical proteomic strategy to identify novel drug targets in Plasmodium falciparum and corresponding lead compounds for the development of new antimalarials
一种化学蛋白质组学策略,用于识别恶性疟原虫中的新药物靶标和相应的先导化合物,用于开发新型抗疟药
- 批准号:
192524457 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Research Grants
Chemisch-proteomische Strategien zur Identifikation krankheitsassoziierter Enzyme in pathogenen Bakterien als neuartige Angriffsziele für Antibiotika
化学蛋白质组学策略识别病原菌中与疾病相关的酶作为抗生素的新靶标
- 批准号:
28198381 - 财政年份:2006
- 资助金额:
-- - 项目类别:
Independent Junior Research Groups
A Proteomic Strategy for Inhibiting Cancer-Associated Enzymes
抑制癌症相关酶的蛋白质组学策略
- 批准号:
5438978 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Emmy Noether International Fellowships
Deciphering the structure activity relationship, mode of action and uptake of isonitrile antibiotics in Gram-negative bacteria
破译革兰氏阴性菌中异腈抗生素的结构活性关系、作用方式和摄取
- 批准号:
505074737 - 财政年份:
- 资助金额:
-- - 项目类别:
Research Grants
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