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.

项目摘要/摘要尽管对根除疟疾的关注越来越大，但预防和治疗仍在由于i）对当前可用的抗疟药的新兴耐药性，包括前线青蒿素 - 基于联合疗法（ACT），ii）缺乏临床有效的疫苗，iii）耐杀虫剂的载体。因此，紧急而持续需要安全，负担得起和新颖可以与寄生虫生命周期的多个阶段打击多个阶段的抗疟药，并具有新的作用机制克服新兴的耐药性。我们已经开发了一种自然产品启发的小说Prodiginine 具有广谱抗性活性的化学型。我们的主要杂质候选人遇到了上述关键要求，例如1）新型化学型； 2）同样有效地针对大型血液阶段恶性疟原虫MDR寄生虫； 3）防止具有根本治愈能力的肝脏阶段感染； 4）有效反对性血液阶段恶性疟原虫的配子细胞； 5）极有可能通过一种新颖的机制运行行动; 6）最佳的体外代谢稳定性和具有快速吸收的体内PK曲线和长期寿命；和 7）可通过低成本生产来综合访问。我们在本申请中提出的拟议工作旨在开发新型抗疟疾质氨酸药物有效，可在多个疟原虫上进行绕过耐药性，并防止疟疾感染复发。该项目的具体目标是进行铅优化研究，以产生新型质毒素的候选者有效，安全性，溶解度和代谢/PK剖面，需要进一步的临床前发展，并研究对选定药物候选药物耐药性的倾向，并确定分子靶标通过整个基因组测序和分析。