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2亿多例恶性疟原虫疟疾临床病例，60多万人死亡，其中90%的死亡发生在撒哈拉以南非洲。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。目前在东南亚出现了对青蒿素类疗法的耐药性。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。美国国立卫生研究院的Sanjay Desai博士证明，通过高通量筛选发现的PSAC抑制剂通过直接作用于该通道来杀死寄生虫。在初步研究中，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，从而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）。化合物也抑制了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”ADME结果，选择两种化学支架进行药物化学优化。第一种是MBX 2366，在第一阶段的SBIR项目中进行了SAR评估。该系列化合物具有高效、低毒和良好的体外ADME特性。二期项目将重点进行铅的优化和放大化学，进一步的作用机制研究，然后进行体内药代动力学和毒理学研究，为药效试验做准备。我们将在人源化SCID小鼠模型中测试优先化合物的功效，该模型将由Medicines for Malaria Venture （MMV）进行。在III期，我们将进行ind的临床前研究，以推进MBX 2366支架中几种最有效和毒性最小的化合物。这一跨学科方法将把MMV的Desai博士和Jeremy Burrows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 200 million clinical cases of P. falciparum malaria and over 600,000 deaths annually, with ninety percent of the deaths occurring in sub-Saharan Africa. 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. Resistance to artemisinin-based therapy is now appearing in Southeast Asia. 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 demonstrated by Dr. Sanjay Desai, NIH, that PSAC inhibitors, discovered by high-throughput screening, kill parasites by direct action on this channel. In preliminary studies, Dr. Desai, developed and applied a screen for PSAC inhibitors using a sorbitol transport assay, which 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 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" ADME results. The first, MBX 2366, was subjected to SAR evaluation in a Phase I SBIR project. Compounds in this series demonstrated efficacy, low toxicity and excellent in vitro ADME properties. The Phase II project proposed here will focus on lead optimizing and scale-up chemistry, further mechanism of action studies and then in vivo pharmacokinetics and toxicology studies in preparation for efficacy testing. We will test the efficacy of prioritized compounds in the humanized SCID mouse model, to be conducted by Medicines for Malaria Venture (MMV). In Phase III, we will conduct IND-enabling preclinical studies to advance several of the most potent and least toxic compounds from the MBX 2366 scaffold. The interdisciplinary approach, which will merge the antimalarial expertise of Dr. Desai and Dr. Jeremy Burrows of MMV 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.