Novel Plasmodial Surface Anion Channel Inhibitors as Antimalarial Drugs

描述（由申请人提供）：该项目的总体目标是通过阻断疟原虫表面阴离子通道（PSAC）的新机制产生新的、有效的、选择性的抗疟药物，PSAC是一种以前未被开发和高度保守的疟原虫靶点。人类疟疾是由疟原虫属的五种原生动物寄生虫引起的。据估计，每年有5亿多例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，几乎所有疟疾死亡都是由它造成的。疟疾寄生虫，最重要的是恶性疟原虫，需要两个宿主，即人类和雌性按蚊。疾病通过被感染的蚊子叮咬传染给人类。目前还没有预防疟疾的有效疫苗，但存在几种小分子治疗方案，如氯喹和青蒿素。CQ曾经是疟疾治疗的主要手段，但由于产生耐药性的突变，它已经失去了大部分功效。迫切需要新的小分子药物，特别是那些针对可能不易产生获得性耐药性的新靶点的药物。PSAC是近年来通过基因鉴定实验验证的新发现的抗疟重要靶点。该通道由寄生虫产生并插入被感染的红细胞膜。最近，通过高通量筛选发现的PSAC抑制剂通过直接作用于该通道而杀死寄生虫。在初步研究中，美国国立卫生研究院的Sanjay Desai博士开发并应用了一种使用山梨醇运输试验筛选PSAC抑制剂的方法，结果鉴定出几种在纳摩尔范围内显示抑制效力的化学型（K0.5 PSAC阻断）。化合物还抑制了低微摩尔到低纳摩尔电位的疟原虫生长（IC50）。根据两种“命中化合物”化学支架的效力、低细胞毒性、易于合成和总体良好的体外“药物样”ADM结果，选择两种化学支架进行药物化学优化。第一种，E912-0081 （MBX 2366）被指定为主要支架，化学合成孔径雷达（SAR）的工作将集中在其上。第二个是C791-0105，如果主要支架不能达到目标1-3中规定的里程碑，它被选为备用支架。I期项目将专注于优化体外特性，如效价、溶解度和预测体内疗效的各种药代动力学参数，并最终确定先导化合物。最佳先导化合物抗疟PSAC抑制剂将进入II期进行体内药代动力学、毒理学和疗效研究。跨学科的方法将把德赛博士的抗疟疾专业知识与Microbiotix的抗感染研究和开发能力结合起来，将为新发现的、必要的和保守的疟疾靶点生产抑制剂，并为耐药感染提供新的治疗选择。

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. PUBLIC HEALTH RELEVANCE: Human malarial disease, caused by parasites of the genus Plasmodium, afflicts 500 million and causes death in one million people per year. Although there are drugs available to treat the disease, resistance is rapidly eroding their efficacy. We propose to develop new antimalarial therapeutic agents that target an unexploited malarial anion channel protein, to combat the growing resistance problem.