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

• 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
• 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

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.

项目概要 在可预见的未来，抗疟药物仍将是全球疟疾管理的支柱。 尽管近年来新的抗疟化合物的研发管线开始看起来很有希望，但 耐药性总是迫在眉睫。这一事实要求我们不断努力发现和开发新的 抗疟药。近年来出现的有前景的新型抗疟化合物包括 破坏恶性疟原虫中 Na+ 的稳态。其中两种化合物（螺吲哚酮和 二氢异喹诺酮）已进入 II 期临床试验，并已证明对 P. 恶性疟原虫和间日疟原虫感染体内寄生虫清除时间甚至比青蒿素更快， 正在使用的起效最快的抗疟药。值得注意的是，至少有 20 种不同的化学类别的化合物， 占药品分发的疟疾和病原体盒中所有抗疟药的约 8% Malaria Venture (MMV) 也有破坏恶性疟原虫 Na+ 稳态的倾向。几行 证据支持这样的观点：所有这些化合物都会抑制寄生虫编码的 Na+ 泵 P 型 ATP 酶 命名为 PfATP4。因此，PfATP4 为广泛的小分子提供了极具吸引力的靶标。 PfATP4 活性化合物能够极快地清除体内寄生虫，这为这些药物带来了希望 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 考虑到青蒿素治疗失败的潜在传播。虽然两种 PfATP4 活性化合物具有 进入临床试验后，药物开发的历史建议谨慎探索备用化合物 考虑管道损耗并减少有价值目标失败的可能性。正是有了这个 我们在此提议开展药物化学活动的背景 符合 MMV 倡导的严格标准的其他临床前候选药物。过去十年我们 开展了广泛的药物化学活动，以确定高效的 PfATP4 活性化合物 与临床研究中的两种化合物属于不同的化学类别。我们的目标是 根据效力、代谢稳定性、理化和性能指导确定临床前候选化合物 恶性疟原虫感染人源化小鼠模型的药代动力学特性、体内功效和安全性 研究。这些研究将与 PK/PD 模拟相结合，以确保化合物满足安全性和 单剂量标准。我们还建议研究通过以下方式最大限度地减少耐药性出现的可能性 探索通过组合不同的化学支架来靶向 PfATP4 的两个不同结构域的效果。

项目成果

Dramatic Consequences of Reducing Erythrocyte Membrane Cholesterol on Plasmodium falciparum.

减少红细胞膜胆固醇对恶性疟原虫的巨大影响。

• 发表时间: 2022-02-23
• 影响因子: 3.7
• 作者: Ahiya, Avantika I;Bhatnagar, Suyash;Morrisey, Joanne M;Beck, Josh R;Vaidya, Akhil B
• 通讯作者: Vaidya, Akhil B

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。

• 发表时间: 2021-09-17
• 影响因子: 4.9
• 作者: Kreutzfeld, Oriana;Rasmussen, Stephanie A;Ramanathan, Aarti A;Tumwebaze, Patrick K;Byaruhanga, Oswald;Katairo, Thomas;Asua, Victor;Okitwi, Martin;Orena, Stephen;Legac, Jennifer;Conrad, Melissa D;Nsobya, Samuel L;Aydemir, Ozkan;Bailey, Jeffrey
• 通讯作者: Bailey, Jeffrey