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

• 批准号: 8832349
• 负责人: Michelle M. Butler
• 金额: $ 64.35万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832349
• 关键词: Accounting; Africa South of the Sahara; Anions; Anopheles Genus; Anti-Infective Agents; Antimalarials; Artemisinins; Bioavailable; Biochemical; Biological Assay; Biological Availability; Cause of Death; Cells; Cessation of life; Chemicals; Chemistry; Chloroquine; Chromosome Mapping; Clinical; Combined Modality Therapy; Culicidae; Cytolysis; DNA; Development; Disease; Disease Resistance; Drug Combinations; Drug Kinetics; Drug resistance; Erythrocyte Membrane; Evaluation; Falciparum Malaria; Family; Female; Genes; Genetic; Goals; Growth; Half-Life; Hour; Human; Human Bites; In Vitro; Infection; Inhibitory Concentration 50; Lead; Liver Microsomes; Malaria; Malaria Vaccines; Mammalian Cell; Measures; Mediating; Medicine; Modeling; Molecular; Mus; Mutation; Oral; Parasites; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Physiological; Plasmodium; Plasmodium falciparum; Poison; Preparation; Property; Protein Isoforms; Proteins; Publishing; Receptor Inhibition; Resistance; Route; Series; Small Business Innovation Research Grant; Solubility; Sorbitol; Southeastern Asia; Structure; Surface; Therapeutic Agents; Therapeutic Index; Time; Toxic effect; Toxicology; Transfection; United States National Institutes of Health; Vaccines; Work; analog; aqueous; artemisinine; base; channel blockers; chemical synthesis; combat; cost; cytotoxicity; design; efficacy testing; extracellular; genotoxicity; high throughput screening; human female; humanized SCID mouse; improved; in vitro Assay; in vivo; indexing; inhibitor/antagonist; interdisciplinary approach; killings; meetings; mouse model; novel; patch clamp; pre-clinical; preclinical study; prevent; public health relevance; research and development; research study; resistance mechanism; resistance mutation; scaffold; scale up; screening; small molecule; uptake

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.

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2亿例恶性疟原虫疟疾临床病例和超过60万例死亡，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。对青蒿素疗法的抗药性目前正在东南亚出现。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。NIH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。化合物还以低纳摩尔效力（IC 50）抑制疟原虫生长。基于其效力、低细胞毒性、合成的易处理性和总体有利的体外“药物样”ADME结果，选择两种“命中化合物”化学支架用于药物化学优化。第一个是MBX 2366，在第一阶段SBIR项目中进行了SAR评估。该系列化合物显示出有效性、低毒性和优异的体外ADME性质。本文提出的II期项目将重点关注铅优化和放大化学，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，为有效性测试做准备。我们将在人源化SCID小鼠模型中测试优先化合物的功效，由疟疾新药研发公司（MMV）进行。在第三阶段，我们将进行IND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。这种跨学科方法将把MMV的Desai博士和Jeremy Burrows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。