Natural Product Inspired Novel Antimalarials with Radical Cure Potential

项目总结/摘要 尽管人们越来越重视消灭疟疾，但对疟疾的预防和治疗仍然是一项艰巨的任务。 困难的原因是：㈠对现有抗疟药物，包括一线青蒿素， 基于联合疗法（ACT），ii）缺乏临床有效的疫苗，iii） 抗病毒载体。因此，对安全、经济、新颖的 具有新的作用机制、可对抗寄生虫生命周期多个阶段的抗疟药物 来克服新出现的抗药性我们已经开发出一种天然产品的灵感新颖的Prodiginine 具有广谱抗疟活性的化学型。我们的首席浪子候选人符合上述条件 关键要求，如1）新的化学型; 2）对一大批血液阶段同样有效 恶性疟原虫MDR寄生虫; 3）预防肝脏期感染，具有根治能力; 4）有效 针对性血阶段恶性疟原虫配子体; 5）极有可能通过一种新的机制， 6）最佳的体外代谢稳定性和体内PK特征，具有快速吸收和长半衰期;和 7)低成本生产合成可得。我们在本申请中提出的工作旨在开发一种 一种新型抗疟药，对多期疟原虫有效， 消除抗药性，防止疟疾复发。该项目的具体目标是 进行先导物优化研究，以产生新型前体素的候选物，其显示增强的口服给药效果。 有效性、安全性、溶解度和代谢/PK特征，保证进一步的临床前开发， 研究对选定候选药物的耐药性倾向，并确定分子靶点 通过全基因组测序和分析。

PROJECT SUMMARY/ABSTRACT Despite the increased attention on the eradication of malaria, prevention and treatment of the disease remain difficult due to i) the emerging resistance to the currently available antimalarials, including front-line artemisinin- based combination therapy (ACT), ii) the absence of a clinically effective vaccine, and iii) the spread of insecticide-resistant vectors. Therefore, there is an urgent and continuous need for safe, affordable and novel antimalarial drugs that can combat multiple stages of the parasite life cycle, with novel mechanism(s) of action to overcome the emerging drug resistance. We have developed a natural product inspired novel prodiginine chemotype with broad-spectrum antimalarial activity. Our lead prodiginine candidate meets the aforementioned key requirements, such as 1) novel chemotype; 2) equally effective against a large panel of blood stage Plasmodium falciparum MDR parasites; 3) prevents liver stage infection with radical cure ability; 4) effective against sexual blood stage P. falciparum gametocytes; 5) highly likely operates by a novel mechanism of action; 6) optimal in vitro metabolic stability and in vivo PK profiles with rapid absorption, and long half-life; and 7) synthetically accessible with low-cost production. Our proposed work in this application seeks to develop a novel antimalarial prodiginine drug that is potent against multiple stages of Plasmodia, with the potential to circumvent drug resistance, and prevent relapsing malaria infection. The specific goal of this project is to conduct lead optimization studies to produce candidates of novel prodiginines that demonstrate enhanced oral efficacy, safety, solubility, and metabolic/PK profiles that warrant further preclinical development, and to investigate the propensity for drug resistance to selected drug candidates and identify the molecular target(s) through whole genome sequencing and analysis.