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Modeling mutant PfCRT-mediated drug transport to predict the emergence of piperaquine-resistant Plasmodium falciparum malaria

模拟突变 PfCRT 介导的药物转运以预测耐哌喹恶性疟原虫疟疾的出现

基本信息

批准号：
10153252
负责人：
Laura Marie Hagenah
金额：
$ 4.6万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153252
关键词：
Affect Africa African African American Alleles Amino Acid Substitution Amodiaquine Anti-malarial drug resistance Antimalarials Area Asia Asians Binding Biological Assay Biophysics Blood Cessation of life Charge Child Chloroquine Chloroquine resistance Clinical Coculture Techniques Combined Modality Therapy Cryoelectron Microscopy Data Drug Efflux Drug Transport Drug resistance Engineering Exhibits Falciparum Malaria Flow Cytometry Genes Genetic Genetic Engineering Geographic Locations Geography Globin Goals Growth Haplotypes Hemoglobin In Vitro Kinetics Knowledge Malaria Malaria Vaccines Mediating Methods Modeling Molecular Morbidity - disease rate Mutation Organelles Parasites Peptide Transport Peptides Pharmaceutical Preparations Physiological Plasmodium falciparum Predisposition Property Protein Biosynthesis Protein Isoforms Recombinant Proteins Regimen Reporter Research Resistance Resolution Risk Role Site South America South American Southeastern Asia Structure Susceptibility Gene System Techniques Testing Therapeutic Time Treatment Protocols Universities Vaccines Vacuole Variant asexual base chemotherapy combat cost disorder control fitness global health insight mortality mutant new combination therapies nonsynonymous mutation novel resistance mutation resistant Plasmodium falciparum resistant strain socioeconomics therapy design therapy development treatment strategy

项目摘要

PROJECT SUMMARY The protozoan parasite Plasmodium falciparum causes over 400,000 malaria deaths each year, mostly in young African children. With no effective vaccine, chemotherapy remains the cornerstone of malaria treatment and control. Malaria eradication efforts have been hindered by the rise of resistance to first-line antimalarials in Southeast Asia, including piperaquine (PPQ, used in combination with dihydroartemisinin). Piperaquine resistance (PPQ-R) and chloroquine resistance are primarily mediated by mutations in the P. falciparum Chloroquine Resistance Transporter (PfCRT). Mutant PfCRT transports drug away from its site of action in the asexual blood stage parasite’s digestive vacuole. This acidic organelle degrades endocytosed host hemoglobin and extrudes globin-derived peptides for parasite protein synthesis. Less understood, however, is how certain amino acid substitutions confer this efflux mechanism and how they impact native transporter function. To investigate the effect of these mutations, I propose in Aim 1 to purify contemporary PPQ-R PfCRT isoforms and perform binding and transport assays with PPQ, other clinically used antimalarials, and positively-charged peptides as proposed natural substrates. These studies will provide a comprehensive functional characterization of PPQ-R PfCRT that is currently lacking. It is also important to predict how PPQ-R could spread to or emerge in other malaria endemic regions. The PfCRT mutations found in SE Asia have yet to be seen on African and South American backgrounds; however, PPQ is being used in these areas including as first-line treatment or for uncomplicated malaria. To predict whether the contemporary amino acid substitutions seen in SE Asia could emerge in other regions to achieve PPQ-R, I propose in Aim 2 to engineer these mutations onto African and South American PfCRT isoforms in P. falciparum parasites from these regions. Assays will quantify the susceptibility of these lines to PPQ and other antimalarials, and determine the relative fitness of each line. The degree of resistance conferred and the fitness cost imposed, along with the regional drug regimen, will be important in determining which pfcrt alleles predominate and which can emerge and spread in areas of PPQ use. These aims are predicated on the hypotheses that (1) PPQ-R mutations in PfCRT alter transport of drugs and natural substrates and that (2) PPQ-R can arise in Africa and South America via the emergence of single amino acid substitutions observed in SE Asia in mutant PfCRT. These data will also identify whether a gain of PPQ-R restores parasite susceptibility to chloroquine, as has been seen with most mutations in SE Asia, thereby creating therapeutic opportunities for new combination therapies. These studies are expected to yield important new insights into the molecular basis for antimalarial drug resistance, and to leverage that knowledge to predict the emergence of novel PPQ-R PfCRT isoforms in distinct geographic regions. This will guide the development of treatment strategies to reduce the global impact and spread of drug-resistant malaria.

项目总结