Apicomplexan Drug Target Discovery

顶复门药物靶点发现

基本信息

批准号：
8567013
负责人：
Ira J Blader
金额：
$ 20.14万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-11 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8567013
关键词：
Adverse effects Affect Alleles Antibiotics Antimalarials Biological Assay Blood Boxing Candidate Disease Gene Cell physiology Chemicals Collection Cryptosporidium parvum Development Drug Targeting Drug resistance Ensure Ethylnitrosourea Experimental Genetics Genes Genetic Screening Genomics Goals Growth Human In Vitro Induced Mutation Infection Inhibitory Concentration 50 Lead Malaria Medicine Mutagenesis Mutagens Mutation Organism Parasites Pathway interactions Patients Pharmaceutical Preparations Plasmodium Plasmodium falciparum Process Processed Genes Proteins Resistance Resistance development Staging Testing Toxic effect Toxoplasma Toxoplasma gondii Vaccines Work cell growth chemical genetics drug sensitivity genetic analysis genome sequencing killings member mutant pathogen prevent public health relevance research study resistance allele resistance mutation screening small molecule

项目摘要

DESCRIPTION (provided by applicant): Apicomplexan parasites include important human pathogens such as Plasmodium spp., Toxoplasma gondii, and Cryptosporidium parvum. Due to a lack of vaccines as well as continuously developing resistance and severe side-effects to currently available treatments, new drugs are needed to treat these infections. While high-throughput small molecule screening has identified numerous anti-malarial lead compounds, it is not known how almost all of these compounds kill Plasmodium. Understanding these mechanisms is important for two key reasons. First, developing a compound into a drug that can be prescribed to patients requires a thorough understanding of the compound's mechanism of action. Second, drugs work by inhibiting cellular compounds and pathways and discovering what these are reveals new drug targets. Because many Apicomplexan-specific processes are essential for growth of these parasites, it is likely that some of lead anti-malarial lead compounds will also affect growth of other Apicomplexan parasites. In this application, we will take advantage of the genetic and experimental tractability of Toxoplasma gondii to identify compounds from the Malaria Box collection that block growth of both Toxoplasma and Plasmodium. We will then use chemical mutagenesis to isolate drug resistant Toxoplasma parasites and identify the mutations that confer drug resistance in Toxoplasma. The drug resistance alleles will then be examined in Plasmodium falciparum to determine which drug resistance genes are conserved and thus represent pan-Apicomplexan drug targets.

描述（由申请人提供）：Apicomplexan寄生虫包括重要的人类病原体，例如疟原虫属，弓形虫弓形虫和隐孢子虫。由于缺乏疫苗以及对当前可用治疗的持续耐药性和严重的副作用，因此需要新药来治疗这些感染。尽管高通量小分子筛选已经鉴定出许多抗疟疾铅化合物，但尚不知道几乎所有这些化合物如何杀死疟原虫。了解这些机制很重要，原因有两个。首先，将化合物开发为可以向患者开处方的药物，需要对化合物的作用机理有透彻的了解。其次，药物通过抑制细胞化合物和途径而起作用，并发现这些是什么揭示了新药靶标。由于许多Apicomplexan特异性过程对于这些寄生虫的生长至关重要，因此某些铅抗疟疾铅化合物可能也会影响其他Apicomplexan寄生虫的生长。在此应用中，我们将利用弓形虫Gondii的遗传和实验性障碍性，从疟疾盒收集中鉴定化合物，从而阻断弓形虫和疟原虫的生长。然后，我们将使用化学诱变来分离耐药性弓形虫寄生虫，并确定赋予毒性抗药性的突变。然后，将在恶性疟原虫中检查耐药性等位基因，以确定哪些耐药性基因是保守的，因此代表了泛磷酸药物靶标。