Reversed Chloroquines as Antimalarial Agents

逆转氯喹作为抗疟药

• 批准号: 7371986
• 负责人: DAVID H PEYTON
• 金额: $ 21.48万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371986
• 关键词: Abbreviations; Address; Antimalarials; Carrier Proteins; Chemicals; Child; Chloroquine; Chloroquine resistance; Class; Combined Modality Therapy; Development; Disease; Dose; Drug Design; Drug resistance; Effectiveness; Erythrocytes; Generations; Goals; Health; Heme; Human; In Vitro; Inhibitory Concentration 50; Investigation; Malaria; Measures; Molecular; Multi-Drug Resistance; Mus; NMR Spectroscopy; Neuraxis; Object Attachment; Optics; Oral; Parasites; Pharmaceutical Preparations; Plasmodium falciparum; Pregnant Women; Research; Resistance; Solubility; Spectrum Analysis; Staging; Structure; Structure-Activity Relationship; Testing; Vacuole; Variant; Work; World Health Organization; base; cost; cytotoxicity; design; hemozoin; in vivo; killings; next generation; novel; quinoline; receptor; response; single molecule; ultraviolet

DESCRIPTION (provided by applicant): The intent of the work presented in this proposal is to address the worldwide health problem brought on by the spread of chloroquine-resistant malaria. An orally available and inexpensive class of replacement drugs termed "reversed chloroquines" (RCQs) is proposed which are expected to act against both chloroquine- resistant and chloroquine-sensitive malaria. Specifically, the following goals are proposed for this research: Goal 1. To understand how to optimize structural features in the next-generation set of RCQ molecules. This will be accomplished by producing a panel of varied RCQ structures, and then testing them against chloroquine-sensitive and chloroquine-resistant malaria, as well as for solubility, central nervous system receptor activity, and cytotoxicity. The most promising candidates will then be evaluated as orally available drugs against malaria in mice. Goal 2. To assess the RCQ mode(s) of action. This will be accomplished by design and testing of RCQ variants which have strategic alterations to the RCQ structures to probe for specific aspects of their action against malaria, by spectroscopic investigations of interactions between heme and RCQs, by inhibition of hemozoin formation, and by measuring the effects on CQ accumulation/efflux of co-administered CQ. After having established the feasibility of the RCQ molecular design, as well providing fundamental understanding of correlations between molecular features and efficacy of RCQs against malaria, the RCQ structures will be "tuned" in order to optimize practical aspects of their use in humans. Although we are directing this study specifically against Plasmodium falciparum, the most problematic human malaria variant, RCQs should also be effective against red blood cell stages of the other human malarias. Malaria is a disease that infects almost half a billion people annually, and kills between one and three million, most of whom are either children or pregnant women. The impact of malaria is increasing, partly because the parasite that causes malaria has evolved into strains that are resistant to our best drugs for treating the disease. This work outlined for this project is to produce and test novel drugs that are designed to circumvent this resistance, as well as to elucidate the way(s) in which these novel drugs work.

描述（由申请人提供）：本提案中提出的工作目的是解决耐氯喹疟疾传播带来的全球健康问题。提出了一种口服且廉价的替代药物，称为“反向氯喹”（RCQ），预计可对抗氯喹耐药性和氯喹敏感型疟疾。具体来说，本研究提出以下目标： 目标 1. 了解如何优化下一代 RCQ 分子的结构特征。这将通过生产一组不同的 RCQ 结构，然后测试它们对氯喹敏感和氯喹耐药的疟疾，以及溶解度、中枢神经系统受体活性和细胞毒性来实现。然后，最有希望的候选药物将被评估为抗小鼠疟疾的口服药物。 目标 2. 评估 RCQ 行动模式。这将通过设计和测试 RCQ 变体来实现，这些变体对 RCQ 结构进行战略性改变，以探究其对抗疟疾作用的具体方面，通过血红素和 RCQ 之间相互作用的光谱研究，通过抑制疟原虫色素形成，并通过测量对共同施用的 CQ 的 CQ 积累/流出的影响。在确定了 RCQ 分子设计的可行性，并提供了对 RCQ 的分子特征和抗疟疾功效之间的相关性的基本了解后，将对 RCQ 结构进行“调整”，以优化其在人类中的实际应用。尽管我们的这项研究专门针对恶性疟原虫（最有问题的人类疟疾变种），但 RCQ 也应该对其他人类疟疾的红细胞阶段有效。疟疾是一种每年感染近 5 亿人并导致 1 至 300 万人死亡的疾病，其中大多数是儿童或孕妇。疟疾的影响正在增加，部分原因是导致疟疾的寄生虫已经进化成对我们治疗该疾病的最佳药物产生抗药性的菌株。该项目概述的这项工作是生产和测试旨在规避这种耐药性的新药，并阐明这些新药的作用方式。