The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites.
The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites.
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DOI：
10.1371/journal.pmed.1001169
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发表时间：
2012-02
期刊：
影响因子：
15.8
通讯作者：
Leroy D
中科院分区：
文献类型：
--
作者：
Delves M;Plouffe D;Scheurer C;Meister S;Wittlin S;Winzeler EA;Sinden RE;Leroy D
Michael Delves 及其同事比较了 50 种当前和实验性抗疟药物对选定人类和非人类寄生虫物种（包括恶性疟原虫、伯氏疟原虫和约氏疟原虫）的肝脏、性血液和蚊虫阶段的活性。疟疾仍然是一种对全球造成毁灭性影响的疾病，每年导致超过 80 万人死亡，其中绝大多数是 5 岁以下的儿童。虽然有有效的治疗方法，但如果要根除疟疾，就需要更广泛的能够针对肝脏和可传播性阶段的小分子疗法。需要这些新药来应对根除疟疾的挑战并规避耐药性。目前的抗疟药主要用于缓解血液阶段的疟疾症状，但人们对更广泛的阶段特异性活性知之甚少。为了克服这一关键差距，我们开发了测定方法来测量抗疟药对疟原虫所有生命阶段的活性，使用多种人类和非人类寄生虫物种，包括恶性疟原虫的雄配子产生（鞭毛）、伯氏疟原虫的动合子发育、伯氏疟原虫和恶性疟原虫的卵囊发育以及疟原虫的肝脏阶段。 约埃利。然后，我们在这些测定中比较了 50 种当前和实验性抗疟药。我们表明，内过氧化物（例如 OZ439）（一种目前处于临床 IIa 期试验的稳定合成分子）是配子体成熟/配子形成并影响孢子生殖的强抑制剂；苯芴醇损害载体的发育； NPC-1161B 是一种新型 8-氨基喹啉，可抑制孢子生殖。这些数据可以针对生命周期的每个阶段对每种化学品类别的优缺点进行客观比较。注意到许多化合物的活性都在可达到的血液浓度范围内，这些结果为决定在下一代抗疟药中组合哪些药物提供了宝贵的指导。这项研究可能揭示对具有复杂生命周期的其他病原体进行全生命周期药物分析的潜力。 请参阅本文后面的编辑摘要 疟疾是一种由疟原虫寄生虫引起的危及生命的疾病，它通过受感染的蚊子叮咬传播给人们。根据最新的全球估计，每年约有 2.5 亿人感染疟疾，约 80 万人死亡，其中大多数是生活在非洲的幼儿。疟疾还会导致儿童严重发病，例如贫血、低出生体重和神经系统问题，这损害了生活在疟疾流行地区的数百万儿童的健康和发育。除了扩大和推广疟疾预防的战略（例如在全国范围内提供杀虫剂处理蚊帐的计划）之外，为了实现根除疟疾的目标，全球卫生界还重新将工作重点放在疟疾的治疗上，包括寻找针对寄生虫生命周期从媒介传播到宿主并返回的不同阶段的新化合物。阻断全球疟疾传播是全球卫生界面临的最大挑战之一。 2011年1月，该杂志发表了关于根除疟疾研究议程（malERA）的系列文章，其中描述了一系列研究和开发优先事项，确定了关键知识差距和所需的必要工具，并介绍了全球根除疟疾的研究和开发议程草案。目前大多数可用的抗疟药物主要针对人类血液系统中致病的寄生虫阶段。但为了根除疟疾，需要新的药物来阻止寄生虫在人类宿主和蚊媒之间的传播，并消除寄生虫在人体内周期的各个阶段。在这项实验室研究中，研究人员比较了所有可用和实验性抗疟药的概况，并分析了每种药物针对疟疾寄生虫生命周期每个特定阶段的活性，以提供一组参考方法和数据，这可能作为基准，帮助指导疟疾研究界评估新发现的抗疟药的潜力。此外，这项分析还可以深入了解哪些化学药物类别可能提供阻断传播的能力——这是根除疟疾的重要组成部分。研究人员在标准化条件下使用新颖的实验室技术开发了一系列新颖的测定方法，以分析 50 种抗疟化合物（现有药物和正在开发的药物）针对三种疟原虫的活性，涵盖疟疾生命周期的每个主要细胞策略，包括耐药寄生虫菌株。在比较分析中，研究人员采用了化学分析方法来识别阻止从宿主向蚊子媒介传播并另外抑制从蚊子向人类宿主传播的药物。研究人员强调了一些令人鼓舞的结果；例如，一些抗疟药对培养的恶性疟原虫和间日疟原虫分离株的无性血液阶段的效力显示出非常好的相关性，这表明恶性疟原虫中抗疟药抑制的大多数途径也可能是间日疟原虫的有效靶标。研究人员还表明，吡咯烷和阿托伐醌等已获批准的药物除了针对无性血液阶段外，还可以针对肝脏和有性阶段。此外，研究人员发现目前正在进行临床试验的新化合物有希望的结果，例如内过氧化物OZ439，这是一种稳定的合成分子，目前正在IIa期临床试验中进行研究，它似乎是配子体成熟和配子形成的强抑制剂。新的 8-氨基喹啉 NPC-1161B 也能抑制孢子生殖。这项分析的结果提供了宝贵的指导，帮助研究人员确定哪些药物和化合物最有希望成为未来潜在的阻断疟疾传播的抗疟药物。这项研究还可以帮助研究人员决定哪些分子可以最好地组合起来，以提供下一代药物，这些药物将成功青蒿素复合疗法并支持根除疟疾。此外，这种全面的药物发现方法可用于测试针对具有复杂生命周期的其他病原体的药物。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.1001169。 malERA 是由 PLoS 于 2011 年 1 月出版的疟疾根除研究议程赞助合集，其中包括 12 篇讨论疟疾研究和开发议程的评论文章
Michael Delves and colleagues compare the activity of 50 current and experimental antimalarials against liver, sexual blood, and mosquito stages of selected human and nonhuman parasite species, including Plasmodium falciparum, Plasmodium berghei, and Plasmodium yoelii. Malaria remains a disease of devastating global impact, killing more than 800,000 people every year—the vast majority being children under the age of 5. While effective therapies are available, if malaria is to be eradicated a broader range of small molecule therapeutics that are able to target the liver and the transmissible sexual stages are required. These new medicines are needed both to meet the challenge of malaria eradication and to circumvent resistance. Little is known about the wider stage-specific activities of current antimalarials that were primarily designed to alleviate symptoms of malaria in the blood stage. To overcome this critical gap, we developed assays to measure activity of antimalarials against all life stages of malaria parasites, using a diverse set of human and nonhuman parasite species, including male gamete production (exflagellation) in Plasmodium falciparum, ookinete development in P. berghei, oocyst development in P. berghei and P. falciparum, and the liver stage of P. yoelii. We then compared 50 current and experimental antimalarials in these assays. We show that endoperoxides such as OZ439, a stable synthetic molecule currently in clinical phase IIa trials, are strong inhibitors of gametocyte maturation/gamete formation and impact sporogony; lumefantrine impairs development in the vector; and NPC-1161B, a new 8-aminoquinoline, inhibits sporogony. These data enable objective comparisons of the strengths and weaknesses of each chemical class at targeting each stage of the lifecycle. Noting that the activities of many compounds lie within achievable blood concentrations, these results offer an invaluable guide to decisions regarding which drugs to combine in the next-generation of antimalarial drugs. This study might reveal the potential of life-cycle–wide analyses of drugs for other pathogens with complex life cycles. Please see later in the article for the Editors' Summary Malaria is a life-threatening disease caused by the Plasmodium parasite, which is transmitted to people through the bites of infected mosquitoes. According to latest global estimates, about 250 million people are infected with malaria every year with roughly 800,000 deaths—most occurring among young children living in Africa. Malaria also causes severe morbidity in children, such as anemia, low birth weight, and neurological problems, which compromise the health and development of millions of children living in malaria endemic areas. In addition to strategies that scale up and roll out the prevention of malaria, such as country-wide programs to provide insecticide-treating bednets, in the goal to eradicate malaria, the global health community has refocused efforts on the treatment of malaria, including finding new compounds that target different stages of the parasite life cycle as it passes from vector to host and back. The interruption of malaria transmission worldwide is one of the greatest challenges for the global health community. In January 2011, this journal published a series on The Malaria Eradication Research Agenda (malERA), which described a set of research and development priorities, identified key knowledge gaps and the necessary tools needed, and introduced a draft research and development agenda for the worldwide eradication of malaria. Most currently available antimalarial drugs primarily target the disease-causing parasites' stages in the human blood system. But to eradicate malaria, new drugs that block transmission of the parasite between the human host and the mosquito vector, and eliminate the various stages of the parasite during its cycle in the human body, are needed. In this laboratory study, the researchers compared the profiles of all available and experimental antimalarials and analyzed each drug for activity against each specific stage in the malaria parasite's life cycle to provide a reference set of methods and data, that might serve as a benchmark to help guide the malaria research community in assessing the potential of newly discovered antimalarials. Furthermore, this analysis could provide insights into which chemical drug classes might provide transmission-blocking capabilities—an essential component of malaria eradication. The researchers used novel laboratory techniques under standardized conditions to develop a series of novel assays to analyze the activities of 50 antimalarial compounds (current drugs and those under development) against three Plasmodium species encompassing every major cellular strategy of the malarial life cycle including drug resistant parasite strains. In their comparative analysis, the researchers undertook a chemical profiling approach to identify the drugs that block transmission from the host to the mosquito vector and additionally suppress transmission from the mosquito to the human host. The researchers highlighted some encouraging results; for example, the potencies of some antimalarials against the asexual blood stage of cultivated P. falciparum and P. vivax isolates show a very good correlation, suggesting that most of the pathways inhibited by antimalarials in P. falciparum may also be valid targets in P. vivax. The researchers also have shown that approved drugs, such as pyronaridine and atovaquone, can target liver and sexual stages in addition to asexual blood stages. Furthermore, the researchers found promising results for new compounds currently in clinical trials, such as the endoperoxide OZ439, a stable synthetic molecule currently being studied in a phase IIa clinical trial, which seemed to be a strong inhibitor of gametocyte maturation and gamete formation. The new 8-aminoquinoline, NPC-1161B, also inhibited sporogony. The results of this analysis provide a valuable guide to help researchers decide which drugs and compounds show most promise as potential future antimalarial drugs for blocking the transmission of malaria. This study could also help researchers make decisions about which molecules could be best combined to provide the next generation of drugs that will succeed artemisinin compound therapy and support the eradication of malaria. Furthermore, this comprehensive approach to drug discovery could be applied to test drugs against other pathogens with complex life cycles. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001169. The malERA a research agenda for malaria eradication sponsored collection, published by PLoS in January 2011, comprises 12 Review articles that discuss agendas in malaria research and development
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影响因子：
3.7
作者：
Coulibaly B;Zoungrana A;Mockenhaupt FP;Schirmer RH;Klose C;Mansmann U;Meissner PE;Müller O
通讯作者：
Müller O
DOI：
10.4269/ajtmh.1990.42.196
发表时间：
1990-03-01
影响因子：
3.3
作者：
COLEMAN, RE
通讯作者：
COLEMAN, RE
DOI：
10.1016/0035-9203(71)90014-9
发表时间：
1971-01-01
影响因子：
2.2
作者：
GERBERG, EJ
通讯作者：
GERBERG, EJ
DOI：
10.1073/pnas.1104063108
发表时间：
2011-07-12
影响因子：
11.1
作者：
Klonis, Nectarios;Crespo-Ortiz, Maria P.;Tilley, Leann
通讯作者：
Tilley, Leann
影响因子：
4.8
作者：
Bhisutthibhan, J;Pan, XQ;Meshnick, SR
通讯作者：
Meshnick, SR