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（由适用提供）：咪唑哌嗪（IZPS）是一种新型的抗疟药，用于治疗简单的疟疾和预防疟疾。 IZP消除了血液阶段感染，并预防疟疾动物模型中的不对称疟疾发育和疟疾传播。该班级的一名成员已在早期临床试验中进行了测试，口服治疗时人类占有良好的耐受性。尽管寄生虫对IZP的抗性是由编码寄生虫疟原虫p.恶性疟原虫循环胺抗性基因座（PFCARL）的突变所赋予的，但IZP的作用机理却尚不很好。因此，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范围的方法，以研究IZP对所有疟原虫生命周期的作用，以使人类的所有疟原虫作用，以确定其精确的目标。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在血液阶段对寄生虫IZP治疗反应。然后，我们将在血液阶段，肝脏和配子细胞中比较这些对IZP的代谢反应与对IZP治疗的转录反应。我们还将针对具有已知作用机理的化合物进行类似的分析，以识别IZP的特定效果。其次，我们将使用完善的体外进化实验管道进行探测任何其他靶标，然后进行整个基因组测序。具有识别抗性突变的基因将与代谢组和转录分析确定的途径有关，以识别推定的靶标。最后，我们将通过一系列O功能研究确认恶性疟原虫中的任何假定靶标。