MOLECULAR TARGETS OF AROMATIC DICATIONIC DRUGS IN FUNGI
真菌中芳香族双阳离子药物的分子靶标
基本信息
- 批准号:5205555
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Cryptococcus neoformans causes a life-threatening human mycoses in
severely immunocompromised hosts such as transplant, cancer, and AIDS
patients. Despite amphotericin B and newer triazoles for treatment, the
management of this infection remains problematic. It is our belief that
the discovery of new antifungal drugs coupled with the elicitation of the
basic molecular mechanisms by which these drugs act are of prime
importance.
Over the past few years the molecular biology of C. neoformans has
significantly expanded. Effective transformation systems have been
developed for C. neoformans and recently in our laboratory gene-knockouts
and plasmid rescue procedures have been accomplished using the biolistic
DNA delivery system. An animal model of cryptococcal meningitis has been
established which closely duplicates the human infection in the central
nervous system and has been used both for molecular studies of virulence
and treatment evaluations.
With this molecular background and the biochemical support of the drug
discovery group, we propose to identify and characterize both
susceptibility and resistance of C. neoformans to aromatic dicationic
compounds at the molecular level. We have found potent fungicidal activity
in vitro with some of these compounds and presently we are screening
classes of these compounds with the biochemists within the group to
identify particular structure-function relationships. Initial molecular
studies will focus on topoisomerase I and II of C. neoformans since recent
studies indicate that they may be the targets of some dicationic agents.
It is probable, however, that some of the new dicationic agents or their
derivatives which have potent fungicidal activities in vitro use other
molecular targets. Therefore, generation of drug-resistant mutants and
restoration of drug susceptibility by gene complementation will be used to
determine if there are other molecular targets of these compounds which
have high affinity for DNA. It is probable that isolation of genes which
restore susceptibility will identify some genes which determine the
entrance and/or interaction of the drug with the target molecule. These
genes or their deduced proteins will give further structure-function
relationships to design selective agents. We expect that by understanding
the molecular targets of these drugs through their interaction with C.
neoformans DNA we will open up new avenues and chemical designs for our
biochemists that may be applicable to other pathogenic fungi. It is of
prime importance that antifungal drugs should have as wide spectrum as
possible but with low host toxicity. The use of molecular biology for the
study of drug targets coupled with the biochemistry of those targeted
genes should allow for custom tailoring new drugs in this class.
加密的新外形导致威胁生命的人真菌
严重免疫功能低下的宿主,例如移植,癌症和艾滋病
患者。尽管有两性霉素B和较新的治疗三唑,但
这种感染的管理仍然有问题。我们的信念是
发现新的抗真菌药物的发现以及引起
这些药物作用为主要的基本分子机制
重要性。
在过去的几年中
大大扩展。有效的转换系统已经
为Neoformans和最近的实验室基因敲除开发
和质粒救援程序是使用生物学完成的
DNA输送系统。一个隐球菌脑膜炎的动物模型已经
建立了密切复制中央人类感染的
神经系统,两者都被用于毒力的分子研究
和治疗评估。
具有这种分子背景和药物的生化支持
发现小组,我们建议识别和表征两者
Neoformans对芳香族性疾病的敏感性和耐药性
分子水平的化合物。我们发现有效的杀真菌活动
在体外与其中一些化合物,目前我们正在筛选
这些化合物与小组中的生物化学家的类别
确定特定的结构功能关系。初始分子
自最近
研究表明,它们可能是某些疾病剂的靶标。
但是,很可能有一些新的dication剂或其
在体外具有有效的杀真菌活动的衍生物使用其他
分子靶标。 因此,产生耐药突变体和
通过基因互补恢复药物易感性将用于
确定这些化合物是否还有其他分子靶标
对DNA具有高亲和力。基因的隔离很可能
恢复易感性将识别一些决定的基因
药物与靶分子的入口和/或相互作用。这些
基因或其推导的蛋白质将提供进一步的结构功能
设计选择性代理的关系。我们希望通过理解
这些药物通过与C的相互作用的分子靶标的。
Neoformans DNA我们将为我们的新途径和化学设计开放
可能适用于其他致病真菌的生物化学家。它是
最重要的是,抗真菌药物应具有与
可能,但宿主毒性低。分子生物学用于
对靶向人的生物化学结合的药物靶标的研究
基因应允许在此类中定制调整新药。
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)

暂无数据
数据更新时间:2024-06-01
JOHN R PERFECT的其他基金
MOLECULAR TARGETS OF AROMATIC DICATIONIC DRUGS IN FUNGI
真菌中芳香族双阳离子药物的分子靶标
- 批准号:60996116099611
- 财政年份:1998
- 资助金额:----
- 项目类别:
MOLECULAR TARGETS OF AROMATIC DICATIONIC DRUGS IN FUNGI
真菌中芳香族双阳离子药物的分子靶标
- 批准号:62171016217101
- 财政年份:1998
- 资助金额:----
- 项目类别:
MOLECULAR TARGETS OF AROMATIC DICATIONIC DRUGS IN FUNGI
真菌中芳香族双阳离子药物的分子靶标
- 批准号:62351006235100
- 财政年份:1997
- 资助金额:----
- 项目类别:
MOLECULAR TARGETS OF AROMATIC DICATIONIC DRUGS IN FUNGI
真菌中芳香族双阳离子药物的分子靶标
- 批准号:37274823727482
- 财政年份:
- 资助金额:----
- 项目类别:
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真菌中芳香族双阳离子药物的分子靶标
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MOLECULAR TARGETS OF AROMATIC DICATIONIC DRUGS IN FUNGI
真菌中芳香族双阳离子药物的分子靶标
- 批准号:62171016217101
- 财政年份:1998
- 资助金额:----
- 项目类别:
MOLECULAR TARGETS OF AROMATIC DICATIONIC DRUGS IN FUNGI
真菌中芳香族双阳离子药物的分子靶标
- 批准号:62351006235100
- 财政年份:1997
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