Novel Plasmodial Surface Anion Channel Inhibitors as Antimalarial Drugs

描述（由申请方提供）：本项目的总体目标是产生新的、有效的、选择性抗疟药，其通过阻断疟原虫表面阴离子通道（PSAC）的新机制发挥作用，PSAC是一种先前未开发的高度保守的疟原虫靶点。人类疟疾是由疟原虫属中的五种原生动物寄生虫引起的。据估计，每年有超过5亿例恶性疟原虫疟疾临床病例和100万例死亡，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，几乎占所有疟疾死亡的原因。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。疾病通过受感染的蚊子叮咬传播给人类。没有有效的疫苗可用于预防疟疾，但存在几种小分子治疗选择，如氯喹（CQ）和青蒿素。CQ曾经是疟疾治疗的支柱，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，特别是那些致力于新靶点的药物，这些药物可能不太容易获得耐药性。PSAC是一个新发现的抗疟重要靶点，最近通过基因鉴定实验得到验证。该通道由寄生虫产生并插入受感染的红细胞膜。最近证明，通过高通量筛选发现的PSAC抑制剂通过直接作用于该通道杀死寄生虫。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转运试验筛选PSAC抑制剂的方法，该方法鉴定了几种在纳摩尔范围内显示抑制效力（K0.5 PSAC阻断）的化学型。化合物还以低微摩尔至低纳摩尔效力（IC 50）抑制疟原虫生长。两种“命中化合物”化学支架被选择用于药物化学优化，基于它们的效力、低细胞毒性、合成的易处理性和总体有利的体外“药物样”ADM结果。第一种，E912-0081（MBX 2366）被指定为主要支架，化学SAR工作将集中在该支架上。如果主支架未能实现目标1-3中规定的里程碑，则选择第二个支架C791-0105作为备用支架。I期项目将专注于优化体外特性，如效力、溶解度和预测体内疗效的各种药代动力学参数，并导致对先导化合物的鉴定。最好的先导化合物抗疟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。跨学科方法将德赛博士的抗疟专业知识与Microbiotix的抗感染研发能力相结合，将为新发现的、重要的和保守的疟疾靶点产生抑制剂，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.