Discovering resistance-resistant antimalarial drug target

发现耐药性抗疟药物靶点

• 批准号: 10741535
• 负责人: Manuel Llinas
• 金额: $ 24.06万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-23 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741535
• 关键词: 5 year old; Address; Anti-malarial drug resistance; Antimalarials; Architecture; Artemisinins; Biochemical; Biological Assay; Blood; Cessation of life; Child; Clinical; Combined Modality Therapy; Culicidae; Dependence; Development; Disease; Dropout; Drug Targeting; Drug resistance; Drug resistance pathway; Environment; Enzymes; Evolution; Exposure to; Future; Genetic; Goals; Growth; Human; Incidence; Individual; Infection; Integration Host Factors; International; Intervention; Life Cycle Stages; Malaria; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Pathway; Metabolism; Modernization; Nutrient; Nutritional; Parasite resistance; Parasites; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Probability; Process; Production; Proliferating; Resistance; Resistance development; Serum; Serum-Free Culture Media; Techniques; Variant; Virulent; asexual; design; drug development; drug discovery; drug resistance development; drug sensitivity; drug-sensitive; empowerment; experience; global health; inhibitor; innovation; knock-down; metabolomics; new therapeutic target; novel; novel strategies; pressure; resistant Plasmodium falciparum; response; small molecule; transmission process; virtual

PROJECT SUMMARY/ABSTRACT Malaria continues to be a major burden on global health, infecting over 220 million and killing over 400 thousand people annually. Although the past fifteen years of enhanced international efforts to eradicate malaria has reduced malaria incidence worldwide, this progress has stagnated in recent years. Antimalarial drugs are foundational in reducing disease and transmission, but resistance has developed within twelve years of clinical introduction to every antimalarial drug developed since 1945 including the current front-line artemisinin-based combination therapies. This ease with which parasites develop resistance clearly indicates that innovative approaches to antimalarial drug discovery are urgently needed. Here we propose two separate strategies designed to discover antimalarial drug targets for which resistance will be difficult to develop in the field. The first approach will characterize metabolic adaptations acquired by malaria parasites upon becoming resistant to a primary drug, with a focus on identifying novel metabolic dependencies (vulnerabilities) of resistant parasites. We propose to employ our extensive experience in metabolomic characterization of the malaria parasite, Plasmodium falciparum, to compare drug-sensitive and drug-resistant parasite biochemical architectures. Metabolomics will be used to elucidate altered metabolic pathways in resistant parasites in order to reveal collateral sensitivities that we will validate as putative drug targets using either small molecule pathway inhibitors or genetic knockdowns of relevant target enzymes. The ultimate goal will be to target these collateral sensitivities together with the primary drug to lock the parasite into a drug-sensitive state, as the adaptations required for primary resistance are no longer available, thus providing an enduring, complementary combination therapy. For the second strategy, we propose to discover host metabolic processes that are critical to support blood-stage development of P. falciparum. The blood stages of the malaria parasite life cycle are responsible for both the symptomology and the human-to- mosquito transmission of the parasite, and critically rely on nutrients from human serum. However, we have found that different human serum lots are highly variable in their ability to support parasite growth and transmission. To identify serum metabolites that correlate with parasite phenotypic readouts, we propose to utilize our metabolomic approaches in combination with standard parasite growth and transmission assays. Using serum lots from healthy donors, this approach will identify naturally variable, and thus potentially targetable, host processes upon which the parasite is reliant. Targeting host factors takes the evolutionary control away from the parasite, reducing the probability of resistance emergence. In all, this proposal seeks to address the persistent problem of antimalarial drug resistance development by evaluating two new strategies for discovering resistance-resistant drug targets.

项目概要/摘要 疟疾仍然是全球健康的主要负担，感染人数超过 2.2 亿，死亡人数超过 400 人 每年数千人。尽管过去十五年来国际社会加强了根除 疟疾已经降低了全世界的疟疾发病率，但近年来这一进展停滞不前。 抗疟药物是减少疾病和传播的基础，但耐药性已经出现 自 1945 年以来开发的每一种抗疟药物在临床引入后的十二年内，包括 当前基于青蒿素的一线联合疗法。寄生虫如此容易生长 耐药性清楚地表明抗疟药物发现的创新方法刻不容缓 需要。在这里，我们提出了两种单独的策略，旨在发现抗疟药物靶点 这种抗性在现场很难产生。第一种方法将表征代谢 疟疾寄生虫在对主要药物产生抗药性后获得的适应，重点是 识别耐药寄生虫的新代谢依赖性（脆弱性）。我们建议聘用 我们在疟原虫代谢组学表征方面拥有丰富的经验 恶性疟原虫，比较药物敏感和耐药寄生虫的生化结构。 代谢组学将用于阐明耐药寄生虫中代谢途径的改变，以便 揭示附带的敏感性，我们将使用任一小分子将其验证为假定的药物靶标 途径抑制剂或相关靶酶的基因敲低。最终目标将是 这些附带敏感性与主要药物一起将寄生虫锁定为药物敏感的状态 状态，因为主要抵抗所需的适应不再可用，从而提供了 持久的、互补的联合疗法。对于第二种策略，我们建议发现主机 对于支持恶性疟原虫血液阶段发育至关重要的代谢过程。血 疟疾寄生虫生命周期的各个阶段对症状和人与人之间的传播都有影响。 蚊子传播寄生虫，并且严重依赖人体血清中的营养。然而，我们 发现不同批次的人血清支持寄生虫生长的能力差异很大 和传输。为了识别与寄生虫表型读数相关的血清代谢物，我们 建议利用我们的代谢组学方法与标准寄生虫生长相结合 传输分析。使用来自健康捐赠者的血清批次，这种方法将自然识别 寄生虫所依赖的宿主进程是可变的，因此可能是可瞄准的。瞄准 宿主因素夺走了寄生虫的进化控制权，降低了耐药性的可能性 的出现。总而言之，该提案旨在解决长期存在的抗疟药物耐药性问题 通过评估两种发现抗药性药物靶标的新策略来进行开发。