Advanced Preclinical Testing of a Broad-Spectrum Antiparasitic Quinolones for Veteran Health

弗吉尼亚州科学家发现了抗寄生虫喹诺酮类药物，它们对疟疾和 弓形虫病。疟疾是一种潜在的致命感染，对退伍军人来说是一种部署风险。众多人 携带艾滋病毒或接受造血干细胞或实体器官移植的退伍军人有患 当他们受到免疫抑制时，会发展成弓形虫脑炎。目前疟疾的治疗方法和 疟疾的预防受到耐药性传播的限制。治疗弓形虫病的药物含量很高 在艾滋病毒和移植患者中更常见和更有问题的副作用发生率。这项建议 基于已确定ELQ-422为主要抗寄生虫喹诺酮类前药的研究，该药对 用于弓形虫病和疟疾的动物模型，在细胞分析和药效实验中无毒。这个 临床前试验的下一步是在动物身上进行药物安全性试验。要做到这一点，最大耐受量 ELQ-422在大鼠身上没有观察到的不良反应水平。展示一种可接受的 ELQ-422在老鼠身上的治疗指数将允许进行大型动物试验和随后的临床试验。ELQ-422 预计是安全的；然而，在发生以下情况时，有必要识别替代的抗寄生虫喹诺酮类药物 ELQ-422没有可接受的治疗指数。ELQ-422对烷氧基碳酸酯的促进剂 这将使ELQ的生物利用度提高近4倍，将适用于有效但受以下限制的ELQ 生物利用度。该促进剂还将应用于一系列ELQ衍生物，这些衍生物将被合成以 优化最近发现的ELQ，它的效力是ELQ-316的100倍，ELQ-316是活跃的 ELQ-422的组件。这些新的前药将在一系列细胞和酶分析中进行测试，以 疗效和毒性，随后进行体内疗效和药代动力学研究。从这些化合物中提取的先导化合物 实验将以与ELQ-422相同的方式在老鼠身上进行安全性评估。最后，ELQ-422及其 活性成分ELQ-316被发现与阿托瓦酮(ATV)在急性心肌梗死模型中具有协同作用 弓形虫病与人类巴贝斯虫病动物模型的耐药性发展 类似疟疾的感染。协同的潜在机制将通过比较 ELQ ATV对寄生虫的杀灭浓度和浓度依赖动力学的比较 单独到每一个院落。此外，ELQS和ATV对彼此的药代动力学效应将是 下定决心。ELQ ATV的协同作用将在体内测试为预防疟疾和对抗潜伏期 弓形虫感染。总体而言，拟议的研究将推动新的广谱抗寄生虫药物的发展。 对喹诺酮类药物进行临床评估，并确定将提高临床适用性的治疗策略 抗寄生虫喹诺酮类药物。

VA scientists have discovered antiparasitic quinolones that are highly effective against malaria and toxoplasmosis. Malaria is a potentially fatal infection that is a deployment hazard for veterans. The many veterans who have HIV or who undergo hematopoietic stem cell or solid organ transplant are at risk of developing Toxoplasma encephalitis when they are immunosuppressed. Current treatments for malaria and prophylaxis for malaria are limited by the spread of drug resistance. Medicines for toxoplasmosis have high rates of side effects that are more common and problematic in HIV and transplant patients. This proposal builds on research that has identified ELQ-422 as a lead antiparasitic quinolone prodrug that is effective in animal models of toxoplasmosis and malaria, and is not toxic in cellular assays and efficacy experiments. The next step in preclinical testing is drug safety testing in animals. To achieve this, the maximum tolerated dose and no observed adverse effect level of ELQ-422 will be determined in rats. Demonstrating an acceptable therapeutic index of ELQ-422 in rats will allow for large animal testing and subsequent clinical trials. ELQ-422 is anticipated to be safe; however, identifying alternate antiparasitc quinolones is necessary in the event that ELQ-422 does not have an acceptable therapeutic index. The alkoxy carbonate ester promoiety of ELQ-422 that increases ELQ bioavailability close to 4 times will be applied to ELQs that were potent but limited by bioavailability. The promoiety will also be applied to a series of ELQ derivatives that will be synthesized to optimize a recently discovered ELQ that is 100 times more potent than ELQ-316, which is the active component of ELQ-422. These new prodrugs will be tested in a cascade of cellular and enzyme assays for efficacy and toxicity followed by in vivo studies of efficacy and pharmacokinetics. Lead compounds from these experiments will be evaluated for safety in rats in the same manner as ELQ-422. Finally, ELQ-422 and its active component ELQ-316 have been found to be synergistic with atovaquone (ATV) in acute models of toxoplasmosis and limit the development of drug-resistance in an animal model of human babesiosis, an infection that is similar to malaria. The underlying mechanism of synergy will be examined by comparing the cytocidal concentration and the concentration dependent kinetics of parasite inhibition of ELQ+ATV compared to each compound alone. In addition, the pharamacokinetic effects of ELQs and ATV on each other will be determined. The synergistic effect of ELQ+ATV will be tested in vivo as malaria prophylaxis and against latent Toxoplasma gondii infection. Overall, the proposed research will advance new broad-spectrum antiparasitic quinolones toward clinical evaluation and define treatment strategies that will enhance the clinical applicability of antiparasitic quinolones.