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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要尽管人们越来越关注根除疟疾，但该疾病的预防和治疗仍然存在困难是由于 i) 对目前可用的抗疟药（包括一线青蒿素）出现的耐药性基于联合疗法 (ACT)，ii) 缺乏临床有效的疫苗，以及 iii) 抗杀虫剂载体。因此，迫切且持续需要安全、实惠、新颖的产品抗疟药物可以对抗寄生虫生命周期的多个阶段，具有新颖的作用机制克服新出现的耐药性。我们开发了一种以天然产品为灵感的新型 prodiginine 具有广谱抗疟活性的化学型。我们的首席候选人符合上述条件关键要求，例如1）新颖的化学型； 2) 对大范围的血期同样有效恶性疟原虫耐多药寄生虫； 3)预防肝期感染并具有根治能力； 4）有效对抗有性血期恶性疟原虫配子细胞； 5）很可能通过一种新颖的机制运作行动; 6）最佳的体外代谢稳定性和体内PK曲线，吸收快，半衰期长；和 7) 合成可得，生产成本低。我们在此应用中提出的工作旨在开发一个新型抗疟药物 prodiginine 有效对抗疟原虫的多个阶段，有潜力规避耐药性，预防疟疾感染复发。该项目的具体目标是进行先导化合物优化研究，以生产出具有增强口服作用的新药物候选物功效、安全性、溶解度和代谢/药代动力学特征，保证进一步的临床前开发，并研究所选候选药物的耐药倾向并确定分子靶标通过全基因组测序和分析。