Expanding the Antimalarial Drug Arsenal-Now, But How?
Expanding the Antimalarial Drug Arsenal-Now, But How?
复制标题
DOI：
10.3390/ph4050681
复制
发表时间：
2011-05-01
期刊：
影响因子：
--
通讯作者：
Mehlotra RK
中科院分区：
文献类型：
--
作者：
Grimberg BT;Mehlotra RK
可用和有效的抗疟疾药物的数量正在迅速减少。这主要是因为疟疾寄生虫基因的一些与耐药性相关的突变，如CRT、mdr1、dhfr/dhps和其他基因突变，导致了对所有已知类别的抗疟疾化合物的广泛耐药性。不幸的是，疟疾寄生虫已经开始在东南亚表现出一定程度的抗药性，甚至对最近引入的药物青蒿素也是如此。虽然有很大的需求，但抗疟疾药物开发管道仍然非常稀薄，化学多样性很小，目前还没有珍贵的青蒿素的替代品。很难预测下一代抗疟疾药物将来自哪里；然而，有六种主要方法：(1)通过替代/轮换或组合方法重新优化现有抗疟疾药物的使用；(2)改变目前用于治疗其他感染或疾病的药物的用途；(3)对现有抗疟疾化合物进行化学修饰；(4)探索自然来源；(5)大规模筛选不同的化学库；以及(6)通过基于寄生虫基因组的(“靶向”)发现。当杨树使用任何新发现的有效抗疟疾治疗方法时，我们必须保持对可能阻碍其成功的寄生虫特异性和人类相关因素的持续警惕。这篇文章既不全面，也不结论。我们的目的是概述抗疟疾药物的耐药性、相关的寄生虫遗传因素(1.介绍；2.恶性疟原虫中青蒿素耐药性的出现)，以及抗疟疾药物开发流水线(3.抗疟疾药物的全球流水线概述)，并突出上述未来抗疟疾治疗方法的一些例子。这些办法可分为“短期”(4.目前可行的备选办法)和“长期”(5.下一代抗疟疾治疗--办法和候选办法)。然而，这两个类别是相互关联的，这两个类别中的方法应该同时实施，同时重点开发成功的、持久的抗疟疾化疗。
The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins. While there is much need, the antimalarial drug development pipeline remains woefully thin, with little chemical diversity, and there is currently no alternative to the precious artemisinins. It is difficult to predict where the next generation of antimalarial drugs will come from; however, there are six major approaches: (i) re-optimizing the use of existing antimalarials by either replacement/rotation or combination approach; (ii) repurposing drugs that are currently used to treat other infections or diseases; (iii) chemically modifying existing antimalarial compounds; (iv) exploring natural sources; (v) large-scale screening of diverse chemical libraries; and (vi) through parasite genome-based (“targeted”) discoveries. When any newly discovered effective antimalarial treatment is used by the populus, we must maintain constant vigilance for both parasite-specific and human-related factors that are likely to hamper its success. This article is neither comprehensive nor conclusive. Our purpose is to provide an overview of antimalarial drug resistance, associated parasite genetic factors (1. Introduction; 2. Emergence of artemisinin resistance in P. falciparum), and the antimalarial drug development pipeline (3. Overview of the global pipeline of antimalarial drugs), and highlight some examples of the aforementioned approaches to future antimalarial treatment. These approaches can be categorized into “short term” (4. Feasible options for now) and “long term” (5. Next generation of antimalarial treatment— Approaches and candidates). However, these two categories are interrelated, and the approaches in both should be implemented in parallel with focus on developing a successful, long-lasting antimalarial chemotherapy.