Novel Plasmodial Surface Anion Channel Inhibitors as Antimalarial Drugs

摘要/摘要 该项目的总体目标是开发新的、有效的、选择性的抗疟疾药物，这些药物通过一种新的 质膜表面阴离子通道(PSAC)的阻断机制 保守的原生生物靶标。人类疟疾是由该属五种原生动物寄生虫引起的 疟原虫。据估计，恶性疟的临床病例超过2亿例。 每年有445,000人死亡，其中大部分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。 疾病通过受感染蚊子的叮咬传播给人类。目前还没有有效的疫苗。 目前有几种小分子治疗方案，如氯喹(CQ)和青蒿素。 CQ曾经是疟疾治疗的中流砥柱，但由于基因突变，它已经失去了很大一部分疗效 抵抗。东南亚现在出现了对青蒿素类药物的抗药性。新型小分子 药物，特别是那些作用于新靶点的药物，可能不太容易产生获得性耐药性， 迫切需要。PSAC是一个新发现的重要抗疟疾靶点，已被基因验证 鉴定实验。该通道由寄生虫产生，并插入受感染的红细胞 薄膜。NIH的Sanjay Desai博士证明，高通量发现的PSAC抑制剂 通过在这个通道上的直接作用来筛选、杀死寄生虫。在初步研究中，德赛博士开发并应用了 用山梨醇转运试验筛选PSAC抑制剂，结果鉴定了几种 在纳摩尔范围内显示抑制能力的化学类型(K0.5PSAC阻断)。化合物也 以低纳摩尔电势抑制原生生物生长(IC50)。“热门化合物”化学支架之一 基于它们的有效性、低细胞毒性、合成的易操作性而被选为药物化学优化的对象 总体来说，在体外“类药物”的ADME结果有利。第一个是MBX 2366，进行了SAR评估 在第一阶段SBIR项目中。该系列化合物在体外表现出高效、低毒和优良的性能。 ADME属性。第二阶段项目的重点是铅优化和扩大化学以及进一步 作用机制研究和良好的体内药代动力学和毒理学研究，以及， 值得注意的是，在人源化的恶性疟原虫感染小鼠模型中的概念验证有效性。建议数 第二阶段项目将最终完成化合物优化，包括将于#年完成的小鼠功效研究。 疟疾药物风险投资(MMV)，选择临床前候选药物，然后进行启用IND的临床前 将一种化合物推向临床的研究。临床前候选药物将被合成成1公斤的规模。这个 跨学科的方法，这将融合德赛博士和杰里米·伯罗斯博士的抗疟疾专业知识 MMV具有MicroBiotix的抗感染研发能力，将生产一种 新的、基本的和保守的疟疾目标，并为耐药感染提供新的治疗选择。

Summary/Abstract The overall objective of this project is to develop 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 445,000 deaths annually, with the majority 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 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, 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 nanomolar potencies (IC50). One of the “hit compound” chemical scaffolds were chosen for medicinal chemistry optimization based on 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 focused on lead optimizing and scale-up chemistry as well as further mechanism of action studies and demonstrated good in vivo pharmacokinetics and toxicology studies and, notably, proof-of-concept efficacy in the humanized mouse model of P. falciparum infection. The proposed Phase IIB project will finalize compound optimization, including murine efficacy studies to be completed by Medicines for Malaria Venture (MMV), select a preclinical candidate and then conduct IND-enabling preclinical studies to advance a compound to the clinic. The preclinical candidate will be synthesized to a 1 Kg scale. 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 novel, essential and conserved malarial target and provide new treatment options for resistant infections.