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

广谱抗寄生虫喹诺酮类药物对退伍军人健康的高级临床前测试

• 批准号: 10265392
• 负责人: Joseph Stone Doggett
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265392
• 关键词: Active Sites; Acute; Adverse reactions; Animal Model; Animal Testing; Animals; Antimalarials; Antiparasitic Agents; Babesiosis; Binding; Bioavailable; Biological Assay; Biological Availability; Blood Tests; Brain; Brain Injuries; Canis familiaris; Carbonates; Caring; Cells; Cellular Assay; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Country; Cyst; Cytochromes b; Dose; Drug Kinetics; Drug resistance; Drug usage; Enzymes; Esters; Event; Formulation; Growth; HIV; Health; Health Personnel; Hematopoietic stem cells; Histopathology; Human; In Vitro; Individual; Infection; K-Series Research Career Programs; Kinetics; Lead; Malaria; Maximum Tolerated Dose; Medicine; Military Personnel; Modeling; Mus; No-Observed-Adverse-Effect Level; Oral; Organ; Organ Transplantation; Parasites; Parasitic Diseases; Parasitic infection; Pharmaceutical Preparations; Plasma; Plasmodium; Plasmodium falciparum; Preclinical Testing; Prodrugs; Property; Prophylactic treatment; Proteins; Provider; Qi; Quinolones; Rattus; Relapse; Research; Risk; Safety; Scientist; Series; Site; Solid; Specificity; Sporozoites; Sprague-Dawley Rats; Stem cell transplant; Structure; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Toxicity Tests; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Transplant Recipients; Transplantation; United States; Veterans; atovaquone; base; brain tissue; clinical application; drug candidate; drug development; drug discovery; drug efficacy; efficacy study; efficacy testing; experimental study; hazard; human model; immunosuppressed; improved; in vivo; in vivo evaluation; intraperitoneal; medication safety; novel therapeutics; pre-clinical; prevent; programs; renal damage; research clinical testing; resistance mutation; safety testing; side effect; stem cells; synergism; toxoplasmic encephalitis; treatment strategy

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.

弗吉尼亚州科学家发现了对疟疾和疟疾非常有效和 弓形虫病。疟疾是一种潜在的致命感染，是对退伍军人的部署危害。许多人 患有艾滋病毒或接受造血干细胞或固体器官移植的退伍军人有可能 免疫抑制时会发育毒素性脑炎。目前对疟疾和 疟疾的预防受到耐药性的限制。弓形虫病的药物较高 在艾滋病毒和移植患者中更常见且有问题的副作用率。这个建议 建立在已经确定ELQ-422是有效的铅喹诺酮前药的研究基础上 弓形虫病和疟疾的动物模型，在细胞测定和功效实验中无毒。这 临床前测试的下一步是动物的药物安全测试。为此，最大耐受剂量 并且在大鼠中未确定ELQ-422的不良影响水平。证明可以接受 ELQ-422在大鼠中的治疗指数将允许进行大型动物测试和随后的临床试验。 ELQ-422 预计会安全；但是，如果必须在 ELQ-422没有可接受的治疗指数。 ELQ-422的烷氧基碳酸酯促进 这增加了ELQ生物利用度接近4次，将应用于有效但受到限制的ELQ 生物利用度。促销活动还将应用于一系列将合成的ELQ衍生物 优化最近发现的ELQ比ELQ-316高100倍，ELQ-316是活动 ELQ-422的组成部分。这些新的前药将在一系列细胞和酶测定中进行测试 功效和毒性，然后是对功效和药代动力学的体内研究。这些铅化合物 实验将以与ELQ-422相同的方式评估大鼠的安全性。最后，ELQ-422及其 已经发现活性成分ELQ-316与Atovaquone（ATV）在急性模型中是协同的 弓形虫病并限制了人类Babesiosis动物模型中药物抗性的发展，这是一种 类似于疟疾的感染。通过比较 比较 单独到每个化合物。此外，ELQ和ATV对彼此的pharamacokinetic效应将是 决定。 ELQ+ATV的协同作用将在体内进行预防疟疾和潜在测试 弓形虫弓形虫感染。总体而言，拟议的研究将推进新的广谱反寄生虫 喹诺酮类用于临床评估并定义将增强临床适用性的治疗策略 抗寄生虫奎诺酮。