Evaluating host-directed therapeutics against blood-stage malaria parasites

评估针对血期疟疾寄生虫的宿主导向疗法

基本信息

批准号：
10528133
负责人：
Manoj T Duraisingh
金额：
$ 19.94万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-14 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10528133
关键词：
Antimalarials Binding Biochemical Biological Assay Biology Blood Bypass CD34 gene CRISPR/Cas technology Cell Culture System Cell Cycle Cell Differentiation process Cell Nucleus Cells Clinical Clinical Trials Development Disease Drug Kinetics Drug Screening Drug resistance Erythrocytes Future Generations Genes Genetic Growth HIV Hematopoietic stem cells Hepatitis Human In Vitro Infection Integration Host Factors Lentivirus Libraries Literature Malaria Methods Molecular Target Morbidity - disease rate Parasites Pharmaceutical Preparations Plasmodium Plasmodium falciparum Podophyllotoxin Positioning Attribute Proteins Proteome RNA Interference Reporting Resistance Resistance development Safety Specificity Therapeutic Toxic effect Validation Virus asexual base chemical genetics cost drug repurposing genetic manipulation global health in vitro Assay indexing inhibitor knock-down mortality mutant next generation operation prevent screening small molecule inhibitor success therapeutic development

项目摘要

Summary Malaria remains a major global health problem, causing tremendous morbidity and mortality. Disease occurs during the blood-stage of human infections with asexual proliferation of Plasmodium parasites in red blood cells (RBCs) leading to their destruction. Due to the evolving threat of drug resistance, there is an urgent need to develop new antimalarials for control and eradication efforts. We hypothesize that host-directed inhibitors (HDIs) will circumvent drug resistance in the parasite, which would have to significantly alter its biology to bypass its requirement for the essential host target. An increasing number of studies have reported RBC-specific inhibitors, but these are poorly validated. We propose to identify and validate HDIs. We will include compounds identified by screening a large drug repurposing library with putative targets in the RBC proteome. To validate host targeting as the antimalarial mechanism of action, we will perform synthetic lethal assays using in vitro cultured RBCs (cRBCs) with knockdown of putative targets. Cellular Thermal Shift Assays will be used to demonstrate direct binding to host targets. Finally, for compounds that appear to be bona fide HDIs, we will assess the ability of the parasite to develop resistance. The establishment of a pipeline to validate host targeting as the mechanism of action of putative HDIs will be a significant advance to the field, supporting the development of host-directed therapeutics in the future.

概括疟疾仍然是一个主要的全球健康问题，导致了巨大的发病率和死亡率。疾病发生在人类感染的血液中，红细胞中疟原虫的无性增殖（RBC）导致其破坏。由于耐药的威胁不断发展，迫切需要开发新的抗疟药来控制和消除工作。我们假设宿主定向抑制剂（HDI）将在寄生虫中规避耐药性，这将不得不显着改变其生物学以绕过其基本主机目标的要求。越来越多的研究报告了RBC特异性抑制剂，但是这些验证良好。我们建议识别和验证HDI。我们将包括确定的化合物通过筛选大型药物重新利用文库，并在RBC蛋白质组中使用推定的靶标。验证主机靶向作用机理，我们将使用体外培养 RBC（CRBC）与推定目标的敲低。蜂窝热移测定将用于证明直接绑定与主机目标。最后，对于似乎是真正的HDI的化合物，我们将评估能力寄生虫发展抗性。建立管道以验证宿主目标作为机制假定的HDI的行动将是该领域的重大进步，支持寄主定向的发展将来的治疗剂。