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新型抗疟候选药物发现与开发的最新进展。

Recent updates in the discovery and development of novel antimalarial drug candidates.

作者信息

Okombo John, Chibale Kelly

机构信息

Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa . Email:

South African Medical Research Council Drug Discovery and Development Research Unit , Department of Chemistry and Institute of Infectious Disease and Molecular Medicine , University of Cape Town , Rondebosch 7701 , South Africa.

出版信息

Medchemcomm. 2018 Feb 2;9(3):437-453. doi: 10.1039/c7md00637c. eCollection 2018 Mar 1.

Abstract

Though morbidity and mortality due to malaria have declined in the last 15 years, emerging resistance to first-line artemisinin-based antimalarials, absence of efficacious vaccines and limited chemotherapeutic alternatives imperil the consolidation of these gains. As a blueprint to steer future designs of new medicines, malaria drug discovery recently adopted a descriptive proposal for the ideal candidate molecules and drugs likely to successfully progress into the final stages of clinical development. As an audit of recent developments in the chemotherapy of malaria in the last five years, this review captures a landscape of diverse molecules at various stages of drug development and discusses their progress. In brief, we also discuss how omics data on has been extensively leveraged to identify potential vaccine candidates and putative targets of molecules in development and clinical use as well as map loci implicit in their modes of resistance. Future perspective on malaria drug development should involve a reconciliation of some of the challenges of the target candidate profiles (TCPs), specifically TCP3, with the promise of effective anti-hypnozoite medicines. Similarly, with the recent development of a humanized mouse model that can evaluate the prophylactic potential of candidate drugs, we argue for increased effort at identifying more liver-stage molecules, which are often only secondarily prioritized in conventional screening programs.

摘要

尽管在过去15年中疟疾导致的发病率和死亡率有所下降,但对一线青蒿素类抗疟药物出现的耐药性、缺乏有效的疫苗以及有限的化疗替代方案危及了这些成果的巩固。作为指导未来新药设计的蓝图,疟疾药物研发最近采用了一项描述性建议,针对可能成功进入临床开发最后阶段的理想候选分子和药物。作为对过去五年疟疾化疗最新进展的一次审视,本综述描绘了处于药物开发各个阶段的各种分子的概况,并讨论了它们的进展。简而言之,我们还讨论了如何广泛利用组学数据来识别潜在的疫苗候选物以及正在开发和临床使用的分子的假定靶点,以及绘制其耐药模式中隐含的基因座。疟疾药物开发的未来前景应包括协调目标候选物概况(TCPs)的一些挑战,特别是TCP3,与有效抗休眠体药物的前景。同样,随着最近能够评估候选药物预防潜力的人源化小鼠模型的开发,我们主张加大力度识别更多的肝期分子,这些分子在传统筛选项目中往往只是次要优先考虑的对象。

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