Diversifying Natural Products via Combinatorial Biosynthesis Methods
通过组合生物合成方法使天然产品多样化
基本信息
- 批准号:6934155
- 负责人:
- 金额:$ 21.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-05-01 至 2010-04-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Cancer causes 1 of every 4 deaths in the US, and it is a critical research goal to optimize available
anticancer drugs and discover and develop fundamentally new, clinically useful ones. Natural products have
an excellent track record as sources of anticancer drugs but traditional natural product drug discovery
approaches face many problems and challenges. As the combinatorial biosynthesis component of the UW
NCDDG program, we propose to produce small libraries of a carefully selected set of promising natural
product leads of micribial origin by genetic manipulations of their biosynthetic pathways. Our hypotheses are:
(1) application of combinatorial biosynthetic methods to the biosynthetic machinery of proven anticancer
drugs will result in the production of novel analogs with an improved therapeutic index; (2) application of
combinatorial biosynthetic methods to biosynthetic machinery of natural products with promising antitumor
activities but unresolved modes of action will generate libraries of the given molecular scaffold, facilitating
the identification of novel targets and leading to the discovery of new classes of anticancer drugs; (3)
engineering of natural product carrier proteins with cancer targeting peptides (CTPs) and/or tumor-specific
activation sites for prodrug design will enable the delivery of the natural product drugs to specific cancer
cells. The long-term goal of this project is to apply combinatorial biosynthetic methods to the various
biosynthetic pathways that have already been characterized in our laboratories for anticancer drug
discovery. The specific aims for this proposal are: (1) engineering and production of novel analogs of natural
product anticancer drugs with known modes of action such as the enediynes C-1027, neocarzinostatin,
maduropetin, calicheamicin, dynamicin, leinamycin, hedamycin, and rebeccamycin; (2) engineering and
production of novel analogs of natural products with promising antitumor activities but unresolved modes of
action such as migrastatin, dorrigocin, lactimidomycin, tautomycin, tautomycetin, and fredericamycin; and (3)
engineering and production of CTP-containing chromoproteins such as C-1027 and neicarzinostatin and of
cathepsin D and matrix-metalloprotease-2 specific prodrugs such as bleomycin and mitomycin C. The
outcomes of these studies will lead to the identification of novel targets for anticancer drug discovery and to
the development of fundamentally new, clinically useful anticancer drugs.
在美国,癌症导致每4例死亡中就有1例死亡,优化现有的癌症治疗方案是一个关键的研究目标。
抗癌药物,并发现和开发从根本上新的,临床上有用的。天然产物
作为抗癌药物来源的良好记录,但传统的天然产物药物发现
各种办法面临许多问题和挑战。作为UW的组合生物合成组件,
NCDDG计划,我们建议产生一个精心挑选的一组有前途的自然
通过对微生物来源的生物合成途径进行遗传操作,我们的假设是:
(1)组合生物合成方法在已证实的抗癌药物生物合成机制中的应用
药物将导致产生具有改善的治疗指数的新型类似物;(2)
组合生物合成方法是一种具有抗肿瘤活性的天然产物的生物合成机制
活性但未解决的作用模式将产生给定分子支架的文库,
新靶点的识别,并导致发现新类别的抗癌药物;(3)
用癌症靶向肽(CTP)和/或肿瘤特异性肽工程化天然产物载体蛋白
用于前药设计的活化位点将使得天然产物药物能够递送至特定的癌症
细胞该项目的长期目标是将组合生物合成方法应用于各种
生物合成途径已经在我们的抗癌药物实验室中得到了表征,
的发现该提案的具体目标是:(1)工程和生产天然的新类似物
具有已知作用模式的产品抗癌药物,例如烯二炔C-1027,新制癌素,
maduropetin、加利车霉素、动力霉素、来那霉素、海达霉素和瑞贝卡霉素;(2)工程化和
具有有希望的抗肿瘤活性但未解决的抗肿瘤模式的天然产物的新类似物的生产
作用如偏头痛抑制素、dorrigocin、lactimidomycin、互变霉素、互变霉素和fredericamycin;和(3)
工程化和生产含CTP的色蛋白,如C-1027和奈替西司他丁,
组织蛋白酶D和基质-金属蛋白酶-2特异性前药如博来霉素和丝裂霉素C。的
这些研究的结果将导致抗癌药物发现的新靶点的鉴定,
开发全新的、临床上有用的抗癌药物。
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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Ben Shen其他文献
Ben Shen的其他文献
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{{ truncateString('Ben Shen', 18)}}的其他基金
Mining Actinomycetal Genomes for Natural Product Discovery and Biosynthesis
挖掘放线菌基因组用于天然产物发现和生物合成
- 批准号:
10640298 - 财政年份:2020
- 资助金额:
$ 21.04万 - 项目类别:
Mining Actinomycetal Genomes for Natural Product Discovery and Biosynthesis
挖掘放线菌基因组用于天然产物发现和生物合成
- 批准号:
10292987 - 财政年份:2020
- 资助金额:
$ 21.04万 - 项目类别:
Mining Actinomycetal Genomes for Natural Product Discovery and Biosynthesis
挖掘放线菌基因组用于天然产物发现和生物合成
- 批准号:
10064144 - 财政年份:2020
- 资助金额:
$ 21.04万 - 项目类别:
Genome Mining for Enediyne Natural Products from Actinomycetals
放线菌烯二炔天然产物的基因组挖掘
- 批准号:
9233171 - 财政年份:2016
- 资助金额:
$ 21.04万 - 项目类别:
A Drug Delivery Strategy for Targeted Therapy of Chronic Lymphocytic Leukemia
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- 批准号:
10377398 - 财政年份:2013
- 资助金额:
$ 21.04万 - 项目类别:
Natural Products from Under-explored Microorganisms
来自未充分探索的微生物的天然产物
- 批准号:
8279187 - 财政年份:2010
- 资助金额:
$ 21.04万 - 项目类别:
Natural Products from Under-explored Microorganisms
来自未充分探索的微生物的天然产物
- 批准号:
7758428 - 财政年份:2010
- 资助金额:
$ 21.04万 - 项目类别:
Platnesimycin and platencin biosynthesis and engineering in antibacterial drugs
Platnesimycin 和 Platencin 的生物合成及其在抗菌药物中的工程
- 批准号:
8132759 - 财政年份:2010
- 资助金额:
$ 21.04万 - 项目类别:
Platnesimycin and platencin biosynthesis and engineering in antibacterial drugs
Platnesimycin 和 Platencin 的生物合成及其在抗菌药物中的工程
- 批准号:
8257191 - 财政年份:2010
- 资助金额:
$ 21.04万 - 项目类别:
Natural Products from Under-explored Microorganisms
来自未充分探索的微生物的天然产物
- 批准号:
8066411 - 财政年份:2010
- 资助金额:
$ 21.04万 - 项目类别:
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