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Advancing gametocytocidal agents as drugs against P. falciparum

推进杀配子细胞药物作为对抗恶性疟原虫的药物

基本信息

批准号：
9059601
负责人：
Kim C Williamson
金额：
$ 39万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9059601
关键词：
Affect Antimalarials Binding Biological Assay Boxing Candidate Disease Gene Cells Clinical Collaborations Complement Coupled Culicidae Data Defect Development Disease Dose Drug Delivery Systems Drug Design Drug Exposure Drug resistance Enzymes Exposure to Expression Library FRAP1 gene Family Funding Genes Germ Cells Goals HepG2 Homologous Gene Hour Human In Vitro Infection Lead Liver Longevity Malaria Metabolic Pathway Modeling Monitor Mus Mutation Oocysts Parasite resistance Parasites Pathway interactions Patients Pattern Peptide Hydrolases Persons Pharmaceutical Preparations Phosphotransferases Plant Resins Plasmodium Plasmodium falciparum Population Production Proteasome Inhibitor Protein-Serine-Threonine Kinases Proteins Recombinant Proteins Reporting Research Personnel Resistance Resistance profile Ribose-Phosphate Pyrophosphokinase Rodent Role Saccharomyces cerevisiae Specificity Sporozoites Staging Structure-Activity Relationship Symptoms Testing Therapeutics for Rare and Neglected Diseases Time Translational Research Transport Process Vesicle Work analog asexual base cytotoxicity test epoxomicin feeding in vitro testing in vivo inorganic phosphate interest killings malaria transmission member miniaturize mouse model novel nucleotide metabolism overexpression protein expression public health relevance research study trafficking transmission process

项目摘要

DESCRIPTION (provided by applicant): New strategies are needed to block malaria transmission and eradicate the spread of the disease. None of the commonly used antimalarials are effective against Plasmodium gametocytes, the parasite stage responsible for transmission, and consequently patients can remain infectious for weeks after symptoms have resolved. Our recent screen of > 6000 bioactive molecules, including 400 malaria box compounds identified 7 with < 50nM IC50 against stage III-V gametocytes. One of these, Torin 2 had an IC50 of 8 nM against P. falciparum strain 3D7, which is >1000 times lower than its activity against the mammalian HepG2 cell line. Torin 2 was also equally effective against 2 additional P. falciparum strains, HB3 and Dd2, with distinct geographic origins and drug resistance profiles. Importantly, two 4mg/kg doses completely blocked oocyst formation using the mouse P. berghei model to test in vivo transmission blocking activity. Early structure activity relationship (SAR) analysis done in collaboration with investigators at the National Center for Advancing Translational Research (NCATS) allowed the production of a Torin 2 resin that lead to the identification of Torin 2 interacting proteins. The goals of this proposal are to extend our analysis of Torin 2 by: Aim 1: Define the stage specificity and timing of Torin 2 inhibition from intraerythrocytic development to sporozoite formation to inform both drug delivery strategies and mechanistic studies. Aim 2: Evaluate the in vivo activity of novel Torin 2 analogs using the rodent malaria model: Aim 3: Evaluate the Plasmodium target and mechanism of Torin 2 gametocytocidal activity using both directed and discovery approaches. In addition, to advancing our currently limited understanding of the cellular pathways required for gametocyte viability, the results will provide important new leads for the development of a potent malaria transmission-blocking drug.