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Discovery of chemically validated malaria liver stage targets

发现经过化学验证的疟疾肝脏阶段目标

基本信息

批准号：
9056361
负责人：
Elizabeth A Winzeler
金额：
$ 46.81万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-06 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9056361
关键词：
Acetyl Coenzyme A Affect Alleles Anabolism Animal Model Antimalarials Artemisinins Biochemistry Biological Assay Blood CRISPR/Cas technology Chemicals Clinical Clinical Trials Culicidae Development Dose Drug Kinetics Drug resistance Evolution Formulation Funding Gene Expression Genes Genome Scan Genomics Goals Growth and Development function Hepatocyte Human Human Volunteers In Vitro Infection Integral Membrane Protein Investigation Laboratories Lead Licensing Liver Malaria Manuscripts Membrane Metabolic Metabolic Pathway Methods Microscopy Midgut Molecular Weight Mus Mutation Oocysts Parasite resistance Parasites Pathway interactions Patients Plasmodium Plasmodium falciparum Plasmodium vivax Preparation Primaquine Property Prophylactic treatment Resistance Running Saccharomyces cerevisiae Safety Series Sporozoites Staging Suppressor Mutations System Testing UDP-galactose transporter Work artemisinine asexual base cyclic amine design digital drug candidate drug development drug discovery drug efficacy feeding genome sequencing genome-wide improved insight malaria transmission member metabolomics nanomolar novel phase II trial prevent public health relevance research study resistance allele resistance gene resistance mutation response scaffold screening shikimate small molecule therapy development transcriptomics treatment response whole genome

项目摘要

DESCRIPTION (provided by applicant): Imidazolopiperazines (IZPs) are a novel class of antimalarial drug in clinical development for the treatment of uncomplicated malaria and malaria prophylaxis. IZPs eliminate blood stage infections and both prevent asymptomatic malaria development and malaria transmission in animal models of malaria. One member of the class has been tested in early clinical trials and is well-tolerated by humans when administered orally. Although parasite resistance to IZPs is conferred by mutations in the Plasmodium falciparum gene encoding the parasite P. falciparum cyclic amine resistance locus (PfCARL), the mechanism of action of the IZP's is not well understood. Further studies on how the IZPs work are therefore needed, We propose to use a suite of genomic methods including metabolomics, transcriptomics and other genome-wide methods to study how IZPs act against all Plasmodium lifecycle forms that parasitize humans, with the goal of identifying their precise target. Specifically, we will first use metabolomics profiling to examine how parasite metabolic pathways respond to parasite IZP treatment in blood stages. We will then compare these metabolic responses to the IZPs to the transcriptional response to IZP treatment in blood stages, liver stages and gametocytes. We will also perform similar analyses against compounds with known mechanisms of action, in order to identify IZP specific effects. Second, we will probe for any additional targets using a well-established experimental pipeline of in vitro evolution followed by whole genome sequencing. Genes with identified resistance mutations will be associated with the pathways identified by metabolomic and transcriptional profiling to identify putative targets. Finally, we will confirm any putative targets in P. falciparum through a series o functional studies.

描述（由申请人提供）：咪唑并哌嗪（IZP）是一类新型抗疟药，处于临床开发阶段，用于治疗无并发症的疟疾和预防疟疾。 IZP 可消除血液阶段感染，并可预防疟疾动物模型中无症状疟疾的发展和疟疾传播。该类药物中的一名成员已在早期临床试验中进行了测试，并且口服给药时人类耐受性良好。虽然寄生虫对 IZP 的抗性是由编码恶性疟原虫环胺抗性基因座 (PfCARL) 的恶性疟原虫基因突变赋予的，但 IZP 的作用机制尚不清楚。因此，需要进一步研究IZP如何发挥作用，我们建议使用一套基因组方法，包括代谢组学、转录组学和其他全基因组方法来研究IZP如何对抗所有寄生于人类的疟原虫生命周期形式，以期确定其精确靶标。具体来说，我们将首先使用代谢组学分析来检查寄生虫代谢途径如何响应血液阶段的寄生虫 IZP 治疗。然后，我们将在血液阶段、肝脏阶段和配子体中比较这些对 IZP 的代谢反应和对 IZP 治疗的转录反应。我们还将对具有已知作用机制的化合物进行类似的分析，以确定 IZP 的具体作用。其次，我们将使用完善的体外进化实验流程，然后进行全基因组测序来探测任何其他目标。具有已确定的抗性突变的基因将与通过代谢组学和转录分析确定的途径相关联，以识别假定的目标。最后，我们将通过一系列功能研究来确认恶性疟原虫中的任何假定目标。