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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：该项目的总体目的是生成新的，有效的选择性抗疟药，这些抗疟药通过阻断质地表面阴离子通道（PSAC）的新型机制，这是一种先前未开发和高度保守的质体靶标。人类疟疾是由质子属中五种原生动物寄生虫引起的。据估计，每年有超过2亿个恶性疟原虫疟疾的临床病例，每年有60万人死亡，其中百分之九十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，它们是人类和雌性蚊子蚊子。疾病是从感染蚊子的咬伤中传播给人类的。没有可预防疟疾的有效疫苗，但是存在几种小分子治疗方案，例如氯喹（CQ）和青蒿素。 CQ曾经是疟疾治疗的主要手段，由于赋予抗性的突变，因此失去了许多功效。目前，基于青蒿素的疗法的抗药性正在东南亚出现。迫切需要新的小分子药物，尤其是那些从事可能不易获得抵抗力的新目标的药物。 PSAC是一个新发现的基本抗疟疾靶标，最近通过基因鉴定实验验证了。该通道是由寄生虫产生的，并将其插入感染的红细胞膜中。 NIH的Sanjay Desai博士证明，通过高通量筛查发现的PSAC抑制剂，通过该渠道的直接行动杀死寄生虫。在初步研究中，Desai博士使用山梨糖醇转运测定法开发并应用了PSAC抑制剂的筛选，这导致鉴定出在纳摩尔范围内显示出抑制性势力（K0.5 PSAC块）的几种化学型。化合物还抑制低纳摩尔势力（IC50）的质量生长。根据其效力，低细胞毒性，合成的障碍和整体有利的体外“类似药物样” ADME结果，选择了两个“命中化合物”化学支架进行药物化学优化。第一个MBX 2366在I期SBIR项目中进行了SAR评估。该系列中的化合物表现出功效，低毒性和出色的体外ADME特性。此处提出的II期项目将重点介绍铅优化和扩展化学，进一步的作用研究机理，然后在体内药代动力学和毒理学研究中进行效果测试。我们将在人源化SCID小鼠模型中测试优先化合物的功效，该模型将由药物进行疟疾风险（MMV）进行。在第三阶段中，我们将进行成分的临床前研究，以从MBX 2366支架中推进几种最有效，最不毒的化合物。跨学科方法将融合Desai博士和MMV的Jeremy Burrows博士的抗疟疾专业知识与微生物群的抗感染研究和开发能力，将为新发现，必不可少的和保守的疟疾靶标生成抑制剂，并为抵抗感染提供新的治疗方法。