Chaparro María Jesús, Calderón Félix, Castañeda Pablo, Fernández-Alvaro Elena, Gabarró Raquel, Gamo Francisco Javier, Gómez-Lorenzo María G, Martín Julio, Fernández Esther
Tres Cantos Medicines Development Campus, DDW , GlaxoSmithKline , Severo Ochoa, 2 , 28760 Tres Cantos , Madrid , Spain.
ACS Infect Dis. 2018 Apr 13;4(4):568-576. doi: 10.1021/acsinfecdis.7b00211. Epub 2018 Jan 24.
Malaria remains a major global health problem. In 2015 alone, more than 200 million cases of malaria were reported, and more than 400,000 deaths occurred. Since 2010, emerging resistance to current front-line ACTs (artemisinin combination therapies) has been detected in endemic countries. Therefore, there is an urgency for new therapies based on novel modes of action, able to relieve symptoms as fast as the artemisinins and/or block malaria transmission. During the past few years, the antimalarial community has focused their efforts on phenotypic screening as a pragmatic approach to identify new hits. Optimization efforts on several chemical series have been successful, and clinical candidates have been identified. In addition, recent advances in genetics and proteomics have led to the target deconvolution of phenotypic clinical candidates. New mechanisms of action will also be critical to overcome resistance and reduce attrition. Therefore, a complementary strategy focused on identifying well-validated targets to start hit identification programs is essential to reinforce the clinical pipeline. Leveraging published data, we have assessed the status quo of the current antimalarial target portfolio with a focus on the blood stage clinical disease. From an extensive list of reported Plasmodium targets, we have defined triage criteria. These criteria consider genetic, pharmacological, and chemical validation, as well as tractability/doability, and safety implications. These criteria have provided a quantitative score that has led us to prioritize those targets with the highest probability to deliver successful and differentiated new drugs.
疟疾仍然是一个重大的全球健康问题。仅在2015年，就报告了超过2亿例疟疾病例，并有超过40万人死亡。自2010年以来，在疟疾流行国家已检测到对当前一线青蒿素联合疗法（ACTs）出现新的耐药性。因此，迫切需要基于新作用模式的新疗法，这些疗法要能像青蒿素一样快速缓解症状和/或阻断疟疾传播。在过去几年中，抗疟领域将努力重点放在了表型筛选上，将其作为一种务实的方法来识别新的有效药物。对几个化学系列的优化工作已取得成功，并确定了临床候选药物。此外，遗传学和蛋白质组学的最新进展已导致对表型临床候选药物进行靶点反卷积。新的作用机制对于克服耐药性和减少损耗也至关重要。因此，一项侧重于识别经过充分验证的靶点以启动有效药物识别计划的补充策略对于加强临床研发流程至关重要。利用已发表的数据，我们评估了当前抗疟靶点组合的现状，重点关注血液期临床疾病。从大量已报道的疟原虫靶点列表中，我们定义了筛选标准。这些标准考虑了遗传、药理和化学验证，以及可处理性/可行性和安全性影响。这些标准提供了一个定量评分，使我们能够优先考虑那些最有可能成功开发出有差异化的新药的靶点。
