Designed Antimalarial Agents Overcoming Chloroquine-Resistance

设计克服氯喹耐药性的抗疟药物

基本信息

批准号：
7220473
负责人：
DAVID H PEYTON
金额：
$ 10.39万
依托单位：
DESIGNMEDIX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-15 至 2009-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The intent of the work presented in this proposal is to counter the worldwide health problem brought on by the spread of chloroquine-resistant malaria. To address the need for an orally available and inexpensive replacement drug, we have developed a novel class of molecules called "reversed chloroquines" (RCQs) which act against both chloroquine-resistant and chloroquine-sensitive malaria. Herein we describe a new sub-class of RCQ molecules, which we term branched RCQ (bRCQ) molecules. These bRCQ molecules may be even better than the 'simple' RCQs. The goal of the described project is to understand how to optimize structural features in the bRCQ molecules to yield the best possible, orally available drug against malaria. This will be accomplished by producing a panel of varied bRCQ structures, and then testing them against chloroquine-sensitive and chloroquine-resistant malaria in red cell culture (an in vitro test), 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. Once these experiments demonstrate the feasibility of the bRCQ molecular design, as well as provide fundamental understanding of correlations between molecular features and efficacy of bRCQs against malaria, the bRCQ structures will be "tuned" in order to optimize practical aspects of their use in humans. Although we are directing this study specifically against P. falciparum, the most problematic human malaria variant, bRCQs should also be effective against the other human malarias. Although there may be a very thin profit margin to be had some 'endemic markets', there is an increasing ability to pay for drugs in countries such as India and China and the military and traveler markets have promise for reasonable commercialization.

描述（由申请人提供）：本提案中提出的工作目的是应对耐氯喹疟疾传播带来的全球健康问题。为了满足对口服且廉价的替代药物的需求，我们开发了一种称为“反向氯喹”（RCQ）的新型分子，它可以对抗氯喹耐药性和氯喹敏感型疟疾。在这里，我们描述了 RCQ 分子的一个新子类，我们将其称为支化 RCQ (bRCQ) 分子。这些 bRCQ 分子可能比“简单”RCQ 更好。所述项目的目标是了解如何优化 bRCQ 分子的结构特征，以产生最佳的口服抗疟疾药物。这将通过生产一组不同的 bRCQ 结构来实现，然后在红细胞培养物中测试它们对氯喹敏感和氯喹耐药的疟疾（体外测试），以及溶解度、中枢神经系统受体活性和细胞毒性。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。一旦这些实验证明了 bRCQ 分子设计的可行性，并提供了对 bRCQ 分子特征和抗疟疾功效之间相关性的基本理解，bRCQ 结构将被“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 bRCQ 也应该对其他人类疟疾有效。尽管某些“流行市场”的利润率可能非常微薄，但印度和中国等国家购买药品的能力不断增强，而且军事和旅游市场有望实现合理的商业化。