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Advancing Fast-acting Antimalarials that Disrupt Na+ Homeostasis in Parasites

开发破坏寄生虫 Na 稳态的速效抗疟药

基本信息

批准号：
10657734
负责人：
Sandhya Kortagere
金额：
$ 74.11万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-12 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657734
关键词：
ATP phosphohydrolase Advocate Ally Antimalarials Artemisinins Biology Chemicals Clinical Trials Collaborations Data Development Dose Drug Kinetics Drug Targeting Drug resistance Ensure Failure Future Genetic Goals Half-Life Homeostasis Human India Infection Injectable International Laboratories Lead Malaria Medicine Metabolic Na(+)-K(+)-Exchanging ATPase Names Parasite resistance Parasites Pharmaceutical Chemistry Pharmacology Phase II Clinical Trials Plasmodium falciparum Plasmodium vivax Population Property Pyrazoles Recording of previous events Research Personnel Resistance Resistance development Safety Series Services Solubility Testing Treatment Failure Work benzimidazole chemical synthesis clinical investigation compliance behavior drug development first-in-human genotoxicity humanized mouse improved in vivo in vivo Model inhibitor lead optimization meter mouse model novel pathogen pharmacokinetics and pharmacodynamics pre-clinical safety study scaffold simulation small molecule

项目摘要

Project Summary For a foreseeable future antimalarial drugs will remain a mainstay for the management of malaria worldwide. While the pipeline of new antimalarial compounds has begun to look promising in recent years, the specter of drug resistance is always looming. This fact demands continued efforts to discover and develop new antimalarial drugs. Among the promising new antimalarial compounds to emerge in recent years are those that disrupt Na+ homeostasis in Plasmodium falciparum. Two of these compounds (a spiroindolone and a dihydroisoquinolone) have progressed to Phase II clinical trials and have shown to be highly potent against P. falciparum and P. vivax infections with in vivo parasite clearance times that are even faster than artemisinin, the fastest acting antimalarial drug in use. Remarkably, at least 20 distinct chemical classes of compounds, comprising ~8% of all antimalarials present in the Malaria and Pathogen Boxes distributed by Medicines for Malaria Venture (MMV), also have the propensity to disrupt Na+ homeostasis in P. falciparum. Several lines of evidence support the notion that all these compounds inhibit a parasite-encoded Na+-pumping P-type ATPase named PfATP4. Thus, PfATP4 presents a highly attractive target for a very broad range of small molecules. Extraordinarily fast clearance of parasites in vivo by PfATP4-active compounds holds the promise for these compounds to emerge as potential replacement for artemisinin, something the world needs to be prepared for given the potential spread of artemisinin treatment failures. While two PfATP4-active compounds have advanced to clinical trials, the history of drug development advises prudence to explore back-up compounds to account for pipeline attrition and mitigating chances of failure against a valuable target. It is with this background that we are proposing here to conduct a medicinal chemistry campaign that would deliver additional preclinical candidates that meet the stringent criteria advocated by MMV. Over the past decade we have carried out extensive medicinal chemistry campaign to identify highly potent PfATP4-active compounds that belong to different chemical classes than the two compounds under clinical investigations. We aim to identify a pre-clinical candidate compound guided by potency, metabolic stability, physicochemical and pharmacokinetic properties, in vivo efficacy in a humanized mouse model of P. falciparum infection and safety studies. These studies will be allied with PK/PD simulations to ensure a compound that meets safety and single dose criteria. We also propose to investigate the possibility of minimizing resistance emergence by exploring the effects of targeting two different domains of PfATP4 by combination of distinct chemical scaffolds.

项目摘要在可预见的未来，抗疟药物仍将是全世界疟疾管理的主要手段。虽然近年来新的抗疟化合物的管道已经开始看起来很有希望，抗药性总是若隐若现。这一事实需要不断努力发现和开发新的抗疟疾药物。近年来出现的有希望的新抗疟化合物包括破坏了恶性疟原虫体内Na+的稳态。这些化合物中的两种（螺吲哚酮和二氢异喹诺酮）已经进展到II期临床试验，并且已经显示出对P. 恶性疟原虫和间日疟原虫感染的体内寄生虫清除时间甚至比青蒿素更快，最快的抗疟疾药物。值得注意的是，至少有20种不同的化合物，占药品分发的疟疾和病原体盒中所有抗疟药的约8%，疟疾风险（MMV）也有破坏恶性疟原虫中Na+稳态的倾向。几行证据支持所有这些化合物抑制寄生虫编码的Na+泵P型ATP酶的观点命名为PfATP 4。因此，PfATP 4为非常广泛的小分子提供了高度有吸引力的靶标。 PfATP 4活性化合物在体内对寄生虫的极快清除为这些药物提供了希望。化合物将成为青蒿素的潜在替代品，世界需要为此做好准备鉴于青蒿素治疗失败的潜在蔓延。虽然两种PfATP 4活性化合物具有在临床试验阶段，药物开发的历史建议谨慎地探索备用化合物，考虑到管道磨损和减少对有价值目标的失败机会。正是基于这种我们在此提议开展一项药物化学运动，符合MMV倡导的严格标准的其他临床前候选药物。在过去的十年里，我们已经开展了广泛的药物化学活动，以确定高效的PfATP 4活性化合物属于与临床研究中的两种化合物不同的化学类别。我们的目标是通过效价、代谢稳定性、物理化学和生物化学指导鉴定临床前候选化合物，在恶性疟原虫感染的人源化小鼠模型中的药代动力学特性、体内功效和安全性问题研究这些研究将与PK/PD模拟相结合，以确保化合物符合安全性，单剂量标准。我们还建议调查最大限度地减少抗性出现的可能性，探索通过组合不同的化学支架靶向PfATP 4的两个不同结构域的效果。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Associations between Varied Susceptibilities to PfATP4 Inhibitors and Genotypes in Ugandan Plasmodium falciparum Isolates.

乌干达恶性疟原虫分离株对 PfATP4 抑制剂的不同敏感性与基因型之间的关联。

DOI：
10.1128/aac.00771-21
发表时间：
2021
期刊：
Antimicrobial agents and chemotherapy
影响因子：
4.9
作者：
Kreutzfeld,Oriana;Rasmussen,StephanieA;Ramanathan,AartiA;Tumwebaze,PatrickK;Byaruhanga,Oswald;Katairo,Thomas;Asua,Victor;Okitwi,Martin;Orena,Stephen;Legac,Jennifer;Conrad,MelissaD;Nsobya,SamuelL;Aydemir,Ozkan;Bailey,Jeffrey
通讯作者：
Bailey,Jeffrey

Dramatic Consequences of Reducing Erythrocyte Membrane Cholesterol on Plasmodium falciparum.