Antimalarial drugs and their useful therapeutic lives: rational drug design lessons from pleiotropic action of quinolines and artemisinins.
Antimalarial drugs and their useful therapeutic lives: rational drug design lessons from pleiotropic action of quinolines and artemisinins.
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DOI：
10.2174/157016310793360693
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发表时间：
2010-11
影响因子：
--
通讯作者：
F. Muregi
中科院分区：
文献类型：
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作者：
F. Muregi
开发有效疟疾疫苗的努力尚未取得成功，因此化疗仍然是疟疾控制战略的主要手段。不幸的是，导致全球约90%疟疾病例的恶性疟原虫正日益对传统抗疟药产生耐药性，因此有必要寻找新的化疗药物，最好是具有新的作用方式。今天，在疟原虫基因组数据库和生物信息学工具的帮助下，随着疟原虫生物学知识的扩展，合理的药物发现策略正在获得新的动力。药物开发是一个费力、耗时和昂贵的过程，因此新药的“有效治疗寿命”（utl）应该与其开发中投入的资源相称。关于经典抗疟药物耐药性的发展和进化的历史证据表明，药物的作用方式影响其UTL。针对单一和特定靶点的药物，如抗疟抗叶酸药和阿托伐醌（ATQ），在临床使用的短时间内就会失效，而具有多效作用的药物，如具有长有效时间的氯喹（CQ）和青蒿素（ART）。不幸的是，目前正在探索开发新药的几乎所有新靶点都属于“特定靶点”，而不是“多靶点”类别，这类药物的utl可能较短。本文将CQ和ART的多效性作用与它们的长UTLs联系起来，并讨论它们与合理药物开发策略的相关性。还探索了可能产生具有长utl的药物的新靶点。
Efforts to develop an effective malarial vaccine are yet to be successful and thus chemotherapy remains the mainstay of malaria control strategy. Unfortunately, Plasmodium falciparum, the parasite that causes about 90% of all global malaria cases is increasingly becoming resistant to classical antimalarials, necessitating a search for new chemotherapeutics preferably with novel modes of action. Today, rational drug discovery strategy is gaining new impetus as knowledge of malaria parasite biology expands, aided by the parasite genome database and improved bioinformatics tools. Drug development is a laborious, time consuming and costly process, and thus the "useful therapeutic lives" (UTLs) of new drugs should be commensurate with the resources invested in their development. Historical evidence on development and evolution of resistance to classical antimalarial drugs shows that the mode of action of a drug influences its UTL. Drugs that target single and specific targets such as antimalarial antifolates and atovaquone (ATQ) are rendered ineffective within a short time of their clinical use, unlike drugs with pleiotropic action such as chloroquine (CQ) and artemisinins (ART) with long UTLs. Unfortunately, almost all new targets currently being explored for development of novel drugs belong to the "specific target" other than the "multiple target" category, and is plausible that such drugs will have short UTLs. This review relates the pleiotropic action of CQ and ART with their long UTLs, and discusses their relevance in rational drug development strategies. Novel targets with potential to yield drugs with long UTLs are also explored.