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Chemoenzymatic synthesis of pradimicin analogues for novel antifungal and antivir

用于新型抗真菌和抗病毒药物的普拉米星类似物的化学酶法合成

基本信息

批准号：
8020871
负责人：
Jixun Zhan
金额：
$ 42.18万
依托单位：
UTAH STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2015-05-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8020871
关键词：
Academic Research Enhancement Awards Adverse effects Amino Sugars Anabolism Anti-Infective Agents Antifungal Agents Antiviral Agents Biochemistry Biological Biological Factors Biology Biomedical Research Cessation of life Chemicals Chemistry Communicable Diseases Development Disease Education Engineering Environment Enzymes Faculty Fostering Glycosides Goals Grant Health Heart Human Infection Joints Knowledge Lead Libraries Malignant Neoplasms Methods Parasites Pathway interactions Public Health Reaction Research Research Personnel Scientist Series Structure Students Testing Therapeutic Training United States National Institutes of Health Universities Utah Virus Work analog base chemical synthesis design drug candidate drug discovery experience fighting glycosyltransferase graduate student improved knowledge base meetings member microorganism novel programs reconstitution sugar water solubility

项目摘要

DESCRIPTION (provided by applicant): Infectious diseases caused by pathogenic microorganisms, viruses or parasites are a major threat to human health, and lead to 16.2% of the world's annual deaths. Discovery of effective therapeutics is urgently needed to fight these diseases and save lives. Pradimicin A is an antifungal and antiviral natural product from Actinomadura hibisca P157-2. Development of pradimicins into anti-infective drugs has been hampered by their poor water solubility and side effects. To take advantage of the significant biological activities of pradimicin A and find promising anti-infective drug candidates, this Academic Research Enhancement Award (AREA) R15 application is to study the biosynthetic pathway of pradimicin A and generate novel pradimicin analogs using both enzymatic and chemical methods. Three central hypotheses for the proposed research are: 1) The complete pradimicin A biosynthetic pathway can be reconstituted and engineered in a heterologous host; 2) Foreign sugar moieties and the corresponding glycosyltransferases can be engineered into the pradimicin biosynthetic pathway; and 3) New pradimicin analogs such as those with different amino sugars have antifungal and antiviral activities. The investigators will test these central hypotheses and accomplish the overall objective of this project by pursuing four specific aims: 1) Investigate the late tailoring steps in the biosynthesis of pradimicin A; 2) Engineer the biosynthesis of novel pradimicin analogs; 3) Chemically synthesize novel pradimicin glycosides; and 4) Evaluate the synthesized pradimicin analogs for antifungal and antiviral activities. With the combination of biosynthetic engineering and chemical synthesis, a series of "unnatural" pradimicin analogs will be generated, which may provide novel lead compounds for new anti- infective drug discovery. The PI and two Co-investigators are from three different departments including biological engineering, chemistry and biochemistry, and biology, respectively. Two graduate and four undergraduate students will perform the proposed research, with assistance from a technician. This multi-departmental collaborative project will provide outstanding training opportunities for student researchers, in accordance with R15 grant objectives. The students will benefit from this interdisciplinary project by working with scientists from different departments and with various backgrounds. It is expected that this project will promote collaborative efforts in biomedical research at Utah State University and the involved students will gain hands-on experience in anti- infective drug discovery. PUBLIC HEALTH RELEVANCE: This project aims to generate a library of novel pradimicin analogs using a combination of enzymatic and chemical methods, and evaluate the antifungal and antiviral activities of these synthesized compounds. The objectives of this proposal are consistent with the goals of the NIH Academic Research Enhancement Award (AREA) R15 program, and will have a significant impact on public health by providing promising molecules for new anti-infective drug discovery. This multi-departmental project will be conducted by a team of researchers consisting of three faculty members, a technician, two graduate students, and four undergraduate students.

描述(申请人提供)：由致病微生物、病毒或寄生虫引起的传染病是对人类健康的主要威胁，并导致全球每年16.2%的死亡。迫切需要发现有效的治疗方法来抗击这些疾病和拯救生命。普拉米星A是放线菌P157-2的一种抗真菌和抗病毒的天然产物。帕拉米星由于其较差的水溶性和副作用，一直阻碍着其成为抗感染药物。为了充分利用普拉米星A的重要生物活性，寻找有前景的抗感染候选药物，本学术研究增强奖(AREA)R15的应用是研究普拉米星A的生物合成途径，并利用酶和化学方法合成新的普拉米星类似物。这项研究的三个中心假设是：1)完整的帕拉米星A生物合成途径可以在异源宿主中重组和工程；2)外源糖段和相应的糖基转移酶可以被改造到帕拉米星生物合成途径中；3)新的帕拉米星类似物，如那些具有不同氨基糖的类似物，具有抗真菌和抗病毒活性。研究人员将验证这些中心假设，并通过追求四个具体目标来实现该项目的总体目标：1)研究普拉米星A生物合成的后期剪裁步骤；2)设计新型普拉米星类似物的生物合成；3)化学合成新型普拉米星糖苷；以及4)评价合成的普拉米星类似物的抗真菌和抗病毒活性。生物合成工程与化学合成相结合，将产生一系列非天然的普拉米星类似物，有望为抗感染新药的开发提供新的先导化合物。PI和两名合作调查员分别来自生物工程、化学和生物化学以及生物学三个不同的系。两名研究生和四名本科生将在一名技术人员的协助下进行拟议的研究。这个多部门合作项目将根据R15的资助目标，为学生研究人员提供出色的培训机会。学生们将通过与来自不同部门和不同背景的科学家合作，从这个跨学科的项目中受益。预计该项目将促进犹他州立大学在生物医学研究方面的合作努力，相关学生将获得抗感染药物发现的实践经验。公共卫生相关性：该项目旨在利用酶和化学方法相结合的方法建立一个新的普拉米星类似物文库，并评估这些合成化合物的抗真菌和抗病毒活性。这项提案的目标与NIH学术研究促进奖(AREA)R15计划的目标一致，并将通过为新的抗感染药物发现提供有前途的分子来对公众健康产生重大影响。这个跨部门的项目将由一个由三名教职员工、一名技术员、两名研究生和四名本科生组成的研究团队进行。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synergistic actions of tailoring enzymes in pradimicin biosynthesis.

DOI：
10.1002/cbic.201402306
发表时间：
2014-10-13
期刊：
CHEMBIOCHEM
影响因子：
3.2
作者：
Napan, Kandy;Zhang, Shuwei;Morgan, Whitney;Anderson, Thomas;Takemoto, Jon Y.;Zhan, Jixun
通讯作者：
Zhan, Jixun

A key cytochrome P450 hydroxylase in pradimicin biosynthesis.