Optimizing Pharmachins for Treatment and Prevention of Drug Resistant Malaria

描述(由申请人提供)： 最严重的、往往是致命的疟疾是由原生动物寄生虫恶性疟原虫引起的。关于每年的死亡人数，疟疾仍然是当今世界上最致命的疾病之一，几千年来一直如此。每年死亡的100万人中，就有数百人因疟疾寄生虫而严重患病。事实上，疟疾是当今世界最常见的疾病和死亡原因之一，尤其是在撒哈拉以南非洲，那里的受害者主要是幼儿和孕妇。由于对包括氯喹在内的多种药物具有抗药性的恶性疟原虫菌株的出现和传播，情况正在恶化。我们发现了一类结构类似于氯喹的新型化合物，它们对耐多药寄生虫具有活性，并且在治疗疟疾感染的小鼠方面非常有效。虽然在疟疾的动物模型中是有效的，但我们相信，我们可以通过结合化学特征来增强对肝脏代谢和崩溃的稳定性，以及旨在减少对这种新类别抗疟疾药物产生耐药性的可能性，来提高我们的主要候选药物PH-128和PH-203的效力和效力。该项目的主要目标是设计抗药性疟疾的新疗法。为了实现我们的目标，我们将使用现代化学方法来设计和合成PH-128和PH-203的结构变体，我们将在组织培养容器中评估每一种抗疟疾寄生虫的新药，以对抗耐药寄生虫和宿主细胞。然后，对这种寄生虫具有高度选择性的药物与氯喹一起在感染疟疾的小鼠身上进行测试，氯喹作为阳性对照。我们假设，通过计划的药物设计、合成和测试的迭代周期，我们将识别并充分描述两种待开发的药素化合物，它们是大型制药公司或非营利性公私合作伙伴关系(如疟疾药物风险投资)的“后期候选药物”。由于耐多药疟疾的广泛性，迫切需要安全有效的替代药物。这些药物有潜力满足这一需求，并对全球健康产生重大影响。由此产生的避免药物中毒、发烧和部署期间复杂的医疗管理的优势也是不言而喻的，对美军士兵的短期和长期健康都有好处。

DESCRIPTION (provided by applicant): The most severe, often fatal, form of malaria is caused by the protozoan parasite Plasmodium falciparum. With regard to the annual toll of people killed, malaria remains one of the deadliest diseases in the world today, as it has been so for thousands of years. For each of the 1 million people killed each year there are hundreds that are severely sickened by malaria parasites. Indeed, malaria is one of the most frequent causes of sickness and death in the world today but especially in sub-Saharan Africa where its victims are primarily young children and pregnant women. And the situation is worsening due to the emergence and spread of strains of P. falciparum that harbor resistance to multiple drugs, including chloroquine. We have discovered a novel class of compounds, structurally similar to chloroquine, that are active against multidrug resistant parasites and they are highly effective in treating malaria infected mice. Although efficacious in the animal model of malaria we believe that we can improve the potency and the efficacy of our lead candidates, PH-128 and PH-203, by incorporating chemical features to enhance stability against liver metabolism and breakdown and other features designed to diminish the likelihood of resistance emerging to this new class of antimalarial agents. The primary objective for this project is to design novel therapeutics for drug resistant malaria. To achieve our objective we will employ modern chemical methods for the design and synthesis of structural variants of PH-128 and PH-203 and we will evaluate each new drug against malaria parasites in tissue culture vessels against drug resistant parasites as well as host cells. Drugs that are highly selective for the parasite are then tested in malaria-infected mice alongside of chloroquine which serves as a positive control. We hypothesize that by the planned iterative cycle of drug design, synthesis, and testing we will identify and fully characterize two pharmachin compounds for development as "late lead candidates" by large pharmaceutical firms or nonprofit public-private partnerships such as the Medicines for Malaria Venture. Due to the widespread nature of multidrug resistant malaria there is an urgent need for safe and effective replacement drugs. The pharmachins have the potential to fulfill this need and to have a major impact on global health. The resultant advantages of avoiding drug toxicity, febrile illness and complex medical management during deployment are also self-evident, as are the benefits to both short and long-term health of the US soldier.