Optimizing ELQs for Treatment and Prevention of Malaria

优化 ELQ 以治疗和预防疟疾

• 批准号: 8776262
• 负责人: Michael Kevin RISCOE
• 金额: $ 61.34万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776262
• 关键词: Antimalarials; Apicomplexa; Atovaquone resistance; Birds; Bite; Blood; Blood Circulation; Cessation of life; Chemicals; Child; Chloroquine; Collaborations; Culicidae; Development; Disease; Doctor of Philosophy; Dose; Drug Targeting; Drug resistance; Drug usage; Employee Strikes; Exhibits; Finches; Floods; Goals; Health; Human; In Vitro; Infection; Inhibitory Concentration 50; Laboratories; Lead; Left; Life Cycle Stages; Liver; Malaria; Malaria prevention; Mammals; Medicine; Meleagris gallopavo; Metabolic; Modeling; Multi-Drug Resistance; Mus; Oral; Parasites; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasmodium; Plasmodium falciparum; Population; Pregnant Women; Prophylactic treatment; Quinolones; Reporting; Resources; Role; Route; Rupture; Serinus; Sporozoites; Staging; Symptoms; Testing; Time; Vivax Malaria; Vulnerable Populations; Work; analog; design; disease transmission; in vivo; interest; killings; male; member; mutant; prevent; programs; prophylactic; quinolone resistance; resistance frequency; resistance mechanism; transmission process; vector mosquito

DESCRIPTION (provided by applicant): Drugs targeting the liver stage offer many advantages over drugs that merely target the blood stage. First, drugs active against the liver stage represent true causally prophylactic agents that can prevent all disease symptoms, including death, associated with malaria. Secondly, it has been established that while wild-caught mosquitoes may harbor thousands of sporozoites, only ~10 sporozoites are transferred in a single bite to the human host. Over the next 2-3 weeks the sporozoite reproduces in the liver to produce 10,000-30,000 descendants before the schizont ruptures and parasites flood into the bloodstream where the absolute parasite burden may increase to ten thousand billion (1013) circulating plasmodia. Clearly it is advantageous to strike at the liver stage where parasite numbers are low, to diminish the likelihood of selecting for a drug resistant mutant and before the infection has a chance to weaken the defenses of the human host. Our primary goal in this project is to develop a non-quinoline drug that is active against P. falciparum and P. vivax malaria, targeting the parasite in the liver and blood stages, and including the gametocytes. Studies (by us and others) have shown that the Endochin-like Quinolone (ELQ) chemotype targets all 3 of these life cycle stages. The ultimate objective of our proposed work is the development of an inexpensive ELQ that can be co-formulated with other antimalarials in a synergistic combination to prevent and treat malaria, and can serve to assist in eradication of the disease worldwide. Our study of endochin, a drug discovered by Andersag in the 1940's) showed that the primary cause of its poor performance in mammals is due to its metabolic instability. More recently we have developed ELQ analogs with subnanomolar IC50 values against multidrug resistant and atovaquone resistant parasites, curative efficacy in murine models of malaria at oral doses of 1mg/kg/day, as well as prophylaxis against sporozoite induced infections at 3mg/kg/day (the lowest dose studied). In this application we seek to continue to explore the chemical space around the quinolone chemotype in order to develop this antimalarial class to the fullest of its potential. As described in the narrative of this proposal e have already discovered an ELQ derivative that is curative in malaria infected mice at 0.1mg/kg/day (4 days) via multiple routes of administration. The Specific Aims of this application are: 1. Lead optimization of ELQ antimalarials, 2. Characterization of the ELQ mechanism(s) of action, and 3. Characterization of ELQ resistance mechanisms and assessment of ELQ resistance frequency in populations of P. falciparum parasites. Development of an ELQ for human use could dramatically change the way in which malaria is managed worldwide. Because ELQs are active against multiple developmental stages of infection they could be used to prevent and treat malaria and also could have a major role in eradicating the disease.

描述（由申请人提供）：针对肝脏阶段的药物比仅针对血液阶段的药物具有许多优势。首先，活跃于肝脏阶段的药物代表了真正的因果预防药物，可以预防与疟疾有关的所有疾病症状，包括死亡。其次，已经确定，尽管野生蚊子可能藏有成千上万的孢子虫，但只有约10个孢子虫被单一咬合转移到人类宿主中。在接下来的2-3周内，孢子虫在肝脏中繁殖，在Schizont破裂和寄生虫泛滥到血液中，产生10,000-30,000个后代，在那里绝对的寄生虫负担可能会增加到一亿（1013）循环质量。显然，在寄生虫数量较低的肝脏阶段进行罢工，从而减少选择耐药突变体的可能性，并且在感染之前有机会削弱人类宿主的防御能力。我们在该项目中的主要目标是开发一种非喹啉药物，该药物活跃于恶性疟原虫和维瓦克斯疟疾疟原虫，靶向肝脏和血液阶段的寄生虫，包括配子细胞。研究（由我们和其他研究）表明，内胆素样喹诺酮（ELQ）化学型针对所有这三个生命周期阶段。我们提出的工作的最终目标是开发廉价的ELQ，可以与其他抗疟药共同成型，以预防和治疗疟疾，并可以帮助消除全球疾病。 我们对Endochin的研究是Andersag在1940年代发现的一种药物）表明，哺乳动物表现不佳的主要原因是由于其代谢不稳定。最近，我们开发了具有抗多药和抗抗抗性抗性寄生虫的亚奈摩尔IC50值的ELQ类似物，在口服疟疾模型中以1mg/kg/day的口服剂量的鼠模型治愈功效，以及预防孢子虫诱导的3mg/kg/kg/kg/kg/kg/kg/kg/day day的sporozoite诱导感染的功效（low Days odse the Loweste depeste sode sode sode sode sode sode sode sode sode de sode sode sode sode）。在此应用中，我们试图继续探索喹诺酮化学型周围的化学空间，以便将这种抗疟疾类别发展到其潜力的最大性。如本提案E的叙述中所述，E已经发现了一种ELQ衍生物，该ELQ衍生物在疟疾感染的小鼠中以0.1mg/kg/天（4天）通过多种给药途径进行了治愈。该应用的具体目的是：1。ELQ抗疟药的铅优化，2。作用ELQ机理的表征，以及3。ELQ抗性机制的表征和评估恶性疟原虫疟原虫群体中ELQ抗性频率的评估。 用于人类使用的ELQ的开发可能会大大改变全球疟疾的管理方式。由于ELQ在感染的多个发育阶段处于活动状态，因此可以用来预防和治疗疟疾，并且在消除该疾病中也可能发挥重要作用。