Novel Plasmodial Surface Anion Channel Inhibitors as Antimalarial Drugs

作为抗疟药物的新型疟原虫表面阴离子通道抑制剂

基本信息

批准号：
8549102
负责人：
Michelle M. Butler
金额：
$ 29.63万
依托单位：
MICROBIOTIX, INC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8549102
关键词：
Accounting Africa South of the Sahara Age Anions Anopheles Genus Anti-Infective Agents Antimalarials Area Artemisinins Biological Assay Cause of Death Cells Cessation of life Chemicals Chemistry Child Chloroquine Chromosome Mapping Clinical Culicidae Cytolysis DNA Development Disease Disease Resistance Drug Combinations Drug Kinetics Drug resistance Drug-sensitive Erythrocyte Membrane Evaluation Exhibits Falciparum Malaria Female Future Genes Goals Growth Human Human Bites In Vitro Infection Inhibitory Concentration 50 Lead Life Cycle Stages Liver Microsomes Malaria Malaria Vaccines Measures Mediating Modeling Mus Mutation Nutrient Oral Parasites Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Plasmodium Plasmodium falciparum Pregnant Women Property Protein Isoforms Proteins Public Health Resistance Risk Small Business Innovation Research Grant Solubility Sorbitol Specificity Structure Surface Therapeutic Agents Toxicology Transfection United States National Institutes of Health Vaccines Work analog aqueous artemisinine base channel blockers combat cytotoxicity design extracellular high throughput screening human female improved in vitro Assay in vivo indexing inhibitor/antagonist interdisciplinary approach killings novel parasite genome pre-clinical prevent research and development research study rural area scaffold screening small molecule statistics

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this project is to generate new, potent, selective antimalarials that act through a novel mechanism of blocking the plasmodial surface anion channel (PSAC), a previously unexploited and highly conserved plasmodial target. Human malaria is caused by five species of protozoan parasites in the genus Plasmodium. It is estimated that there are more than 500 million clinical cases of P. falciparum malaria and one million deaths annually, with ninety percent of the deaths occurring in sub-Saharan Africa. By far the most dangerous of these is P. falciparum, which accounts for nearly all malaria deaths. The malaria parasites, most importantly P. falciparum, require two hosts, which are humans and female Anopheles mosquitoes. Disease is transmitted to humans from the bite of an infected mosquito. There are no effective vaccines available to prevent malaria, but several small molecule treatment options exist, such as chloroquine (CQ) and artemisinin. CQ, once the mainstay of malaria treatment, has lost much of its efficacy because of mutations that confer resistance. New small molecule drugs, especially those working on new targets that may be less susceptible to acquired resistance, are desperately needed. PSAC is a newly discovered essential antimalarial target which was recently validated by gene identification experiments. The channel is produced by the parasite and inserts into the infected erythrocyte membrane. It was recently demonstrated that PSAC inhibitors, discovered by high-throughput screening, kills parasites by direct action on this channel. In preliminary studies, Dr. Sanjay Desai, NIH, developed and applied a screen for PSAC inhibitors using a sorbitol transport assay, that resulted in the identification of several chemotypes that displayed inhibitory potencies (K0.5 PSAC block) in the nanomolar range. Compounds also inhibited plasmodial growth with low micromolar to low nanomolar potencies (IC50). Two of the "hit compound" chemical scaffolds were chosen for medicinal chemistry optimization on the basis of their potency, low cytotoxicity, tractability of synthesis and overall favorable in vitro "drug-like" ADM results. The first, E912-0081 (MBX 2366) was designated as the primary scaffold, upon which chemistry SAR efforts will be focused. The second, C791-0105, has been selected as a backup scaffold should the primary scaffold fail to achieve the milestones set forth in Aims 1-3. The Phase I project will focus on optimizing in vitro properties such as potency, solubility and variou pharmacokinetic parameters predictive of in vivo efficacy and leading to identification of a lead compound(s). The best lead compound antimalarial PSAC inhibitors will then progress to Phase II for in vivo pharmacokinetics, toxicology and efficacy studies. The interdisciplinary approach, which will merge the antimalarial expertise of Dr. Desai with the anti-infective research and development capabilities of Microbiotix, will produce inhibitors for a newly discovered, essential and conserved malarial target and provide new treatment options for resistant infections.

描述（由申请人提供）：该项目的总体目的是生成新的，有效的选择性抗疟药，这些抗疟药通过阻断质地表面阴离子通道（PSAC）的新型机制，这是一种先前未开发和高度保守的质体靶标。人类疟疾是由质子属中五种原生动物寄生虫引起的。据估计，每年有超过5亿的恶性疟原虫疟疾临床病例和100万人死亡，其中90％的死亡发生在撒哈拉以南非洲。到目前为止，其中最危险的是恶性疟原虫，它几乎占所有疟疾死亡。疟疾寄生虫，最重要的是恶性疟原虫，需要两个宿主，它们是人类和雌性蚊子蚊子。疾病是从感染蚊子的咬伤中传播给人类的。没有可预防疟疾的有效疫苗，但是存在几种小分子治疗方案，例如氯喹（CQ）和青蒿素。 CQ曾经是疟疾治疗的主要手段，由于赋予抗性的突变，因此失去了许多功效。迫切需要新的小分子药物，尤其是那些从事可能不易获得抵抗力的新目标的药物。 PSAC是一个新发现的基本抗疟疾靶标，最近通过基因鉴定实验验证了。该通道是由寄生虫产生的，并将其插入感染的红细胞膜中。最近证明，高通量筛选发现的PSAC抑制剂通过该通道上的直接作用杀死寄生虫。在初步研究中，NIH的Sanjay Desai博士使用山梨糖醇转运测定法开发并应用了PSAC抑制剂的屏幕，这导致鉴定出在纳米尔范围内显示出抑制性效力（K0.5 PSAC块）的几种化学型。化合物还抑制了低微摩尔至低纳摩尔势力（IC50）的质子生长。根据其效力，低细胞毒性，合成的障碍和整体有利的体外“类似药物样”的结果，选择了两个“命中化合物”化学支架进行药物化学优化。第一个，E912-0081（MBX 2366）被指定为主要支架，将化学SAR努力集中在其上。第二个C791-0105被选为备用支架，如果主要脚手架未能达到AIMS 1-3中规定的里程碑，则被选为备用支架。第一阶段项目将着重于优化体外特性，例如效力，溶解度和Variou Pharmacacinetic参数，可预测体内功效，并导致识别铅化合物（S）。然后，最好的铅复合抗疟疾PSAC抑制剂将发展为体内药代动力学，毒理学和有效性研究的II期。跨学科方法将使Desai博士的抗疟疾专业知识与微生物群的抗感染研发能力合并，将为新发现，必不可少的和保守的疟疾靶标生成抑制剂，并为抵抗感染提供新的治疗方法。