Natural Product Inspired Novel Antimalarials with Radical Cure Potential

受天然产物启发的具有根治潜力的新型抗疟药

• 批准号: 10635649
• 负责人: JANE X KELLY
• 金额: $ 65.64万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-04 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635649
• 关键词: Age; Antimalarials; Artemisinins; Attention; Biological Assay; Biological Availability; Blood; Cessation of life; Child; Clinical; Combined Modality Therapy; Cytochrome P450; DNA analysis; Disease; Drug Interactions; Drug Kinetics; Drug resistance; Effectiveness; Evaluation; Genomic DNA; Glucosephosphate Dehydrogenase Deficiency; Goals; Half-Life; In Vitro; Infection; Insecticide Resistance; Isoenzymes; Lead; Life Cycle Stages; Liver; Malaria; Measurement; Metabolic; Microsomes; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Oral; Parasites; Patients; Permeability; Pharmaceutical Preparations; Plasmodium; Plasmodium berghei; Plasmodium cynomolgi; Plasmodium falciparum; Plasmodium vivax; Plasmodium yoelii; Pregnant Women; Prevention; Production; Public Health; Relapse; Research Project Grants; Resistance; Rodent; Safety; Solubility; Time; Toxic effect; Toxicity Tests; Tropical Disease; Vaccines; Validation; Work; World Health Organization; absorption; bioluminescence imaging; chemical synthesis; combat; cost; drug candidate; genome analysis; genome sequencing; improved; in vivo; in vivo evaluation; iterative design; lead candidate; lead optimization; liver imaging; malaria infection; metabolic profile; mortality; natural product inspired; nonhuman primate; novel; novel therapeutics; preclinical development; prevent; process optimization; prodiginine; relapse prevention; small molecule libraries; vector; whole genome

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.

项目摘要/摘要 尽管人们越来越重视根除疟疾，但预防和治疗这一疾病的工作仍在继续。 困难的原因是：一)目前可用的抗疟疾药物，包括一线青蒿素--出现了新的耐药性-- 基于联合疗法(ACT)，二)缺乏临床有效的疫苗，以及三)传播 抗杀虫剂媒介。因此，对安全、负担得起和新颖的需求是迫切和持续的 抗疟疾药物可以对抗寄生虫生命周期的多个阶段，具有新的作用机制(S) 以克服新出现的抗药性。我们开发了一种以天然产品为灵感的新颖的Prodiginine 具有广谱抗疟疾活性的化学型。我们领先的Prodiginine候选人遇到了前面提到的 关键要求，例如1)新的化学类型；2)对大的血液阶段同样有效 恶性疟原虫多药耐药寄生虫；3)根治能力预防肝期感染；4)有效 抗有性血液期恶性疟原虫配子体；5)很可能是通过一种新的机制工作的 作用；6)最佳的体外代谢稳定性和体内PK谱，吸收快，半衰期长；以及 7)综合可及，生产成本低。我们在此应用程序中提议的工作旨在开发一种 一种新的抗疟疾前列腺素药物，对多阶段的疟原虫有效，具有潜在的 规避抗药性，防止疟疾复发感染。这个项目的具体目标是 进行先导优化研究，以产生显示增强口腔功能的新型Prodiginine候选药物 保证进一步临床前开发的有效性、安全性、溶解性和代谢/PK特征，以及 调查对选定候选药物的耐药倾向并确定分子靶点(S) 通过全基因组测序和分析。