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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：
10062806
负责人：
Michelle M. Butler
金额：
$ 98.25万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062806
关键词：
Africa South of the Sahara Anions Anopheles Genus Anti-Infective Agents Antimalarials Artemisinins Bioavailable Biochemical Biological Assay Biological Availability Biology Blood Circulation Canis familiaris Cause of Death Cells Cessation of life Chemicals Chemistry Chloroquine Chromosome Mapping Clinic Clinical Clinical Trials Collaborations Combined Modality Therapy Culicidae Cytolysis DNA Dangerousness Development Disease Disease Resistance Drug Combinations Drug Kinetics Drug resistance Electrophysiology (science)Erythrocyte Membrane Evaluation Falciparum Malaria Female Formulation Future Generations Genes Genetic Geography Goals Growth Half-Life Hour Human Human Bites In Vitro Infection Liver Microsomes Malaria Malaria Vaccines Mammalian Cell Measures Mediating Medicine Modeling Molecular Mus Mutation National Institute of Allergy and Infectious Disease Oral Parasite resistance Parasites Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Study Phase Plasmodium Plasmodium falciparum Plasmodium ovale Plasmodium vivax Property Proteins Publishing Rattus Reporting Resistance Route Safety Series Serum Small Business Innovation Research Grant Solubility Sorbitol Southeastern Asia Surface Therapeutic Therapeutic Index Time Toxic effect Toxicology Transfection United States National Institutes of Health Vaccines analog base chemical synthesis clinical candidate clinical development combat cost cytotoxicity design efficacy study experimental study extracellular high throughput screening human female humanized mouse improved in vivo inhibitor/antagonist interdisciplinary approach lead optimization lead series mouse model nanomolar novel patch clamp pre-clinical preclinical development preclinical study prevent protein complex research and development resistance mechanism resistance mutation scaffold scale up screening small molecule targeted treatment uptake vaccine access

项目摘要

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.

摘要/摘要该项目的总体目标是开发新的、有效的、选择性的抗疟药，通过新颖的机制发挥作用。阻断疟原虫表面阴离子通道（PSAC）的机制，这是一种以前未开发的且高度保守的疟原虫靶标。人类疟疾是由该属的五种原生动物寄生虫引起的疟原虫。据估计，恶性疟临床病例超过2亿例及以上每年有 445,000 人死亡，其中大部分死亡发生在撒哈拉以南非洲地区。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。没有有效的疫苗预防疟疾，但存在几种小分子治疗选择，例如氯喹 (CQ) 和青蒿素。 CQ 曾经是疟疾治疗的中流砥柱，但由于突变导致其失去了大部分功效。反抗。东南亚目前正在出现对青蒿素疗法的耐药性。新型小分子药物，特别是那些作用于可能不易受到获得性耐药性的新靶点的药物，迫切需要。 PSAC是新发现的重要抗疟靶标，并已通过基因验证鉴定实验。该通道由寄生虫产生并插入受感染的红细胞膜。 NIH 的 Sanjay Desai 博士证明，PSAC 抑制剂是通过高通量发现的通过直接作用于该通道来筛选、杀死寄生虫。在初步研究中，德赛博士开发并应用了使用山梨醇转运测定筛选PSAC抑制剂，结果鉴定了几种在纳摩尔范围内表现出抑制效力（K0.5 PSAC 块）的化学型。化合物也以低纳摩尔效力 (IC50) 抑制疟原虫生长。 “热门化合物”化学支架之一基于其效力、低细胞毒性、合成的易处理性而被选择进行药物化学优化以及总体良好的体外“类药物”ADME 结果。第一个MBX 2366接受了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、低毒和优异的性能 ADME 属性。第二阶段项目的重点是先导化合物优化和放大化学以及进一步作用机制研究并证明了良好的体内药代动力学和毒理学研究，值得注意的是，在恶性疟原虫感染的人源化小鼠模型中进行了概念验证。拟议的 IIB 期项目将完成化合物优化，包括将于 2017 年完成的小鼠功效研究 Medicines for Malaria Venture (MMV)，选择临床前候选药物，然后进行支持 IND 的临床前研究将化合物推向临床的研究。临床前候选药物将被合成至 1 公斤规模。这跨学科方法，将融合 Desai 博士和 Jeremy Burrows 博士的抗疟专业知识 MMV 凭借 Microbiotix 的抗感染研发能力，将生产用于新颖、重要且保守的疟疾靶标，并为耐药感染提供新的治疗选择。