Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads.
Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads.
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DOI：
10.1124/molpharm.122.000549
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发表时间：
2022-09-01
影响因子：
3.6
通讯作者：
Desai, Sanjay A
中科院分区：
文献类型：
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作者：
Butler, Michelle M;Waidyarachchi, Samanthi L;Desai, Sanjay A
人类和动物疟疾寄生虫通过寄生虫相关离子通道介导增加其宿主红细胞对广泛溶质的渗透性。分子和药理学研究表明，这种抑制剂在寄生虫获取营养方面发挥着重要作用，但目前还缺少适合开发抗疟药物的抑制剂。在这里，我们使用恶性疟原虫（一种致命的人类病原体）和MBX-2366（一种来自高通量筛选的纳摩尔亲和力哒嗪酮抑制剂）的衍生物产生了一种有效和特异性的药物。由于这种筛选缺乏体内功效所需的生物利用度和稳定性，我们合成了315种衍生物，以优化药物样性质，建立靶标特异性，并保留对寄生虫诱导的渗透性的有效活性。使用强大的迭代管道，我们生成了MBX-4055，这是一种对不同人类寄生虫菌株具有活性的衍生物。MBX-4055具有改善的口服吸收，具有可接受的体内耐受性和药代动力学。它也对35种人体通道和受体的电池没有活性，并且在体外选择期间难以获得抗性。单分子和单细胞膜片钳表明对疟原虫表面阴离子通道的直接作用，该通道与寄生虫编码的RhopH蛋白相关联。这些研究确定了哒嗪酮作为具有明确作用机制的新型和易处理的抗疟支架。重要性声明：由于抗疟药物在致命的人类恶性疟原虫病原体中容易产生耐药性，因此需要新的治疗方法。这项研究现在已经开发了一种新型的类药物系列的哒嗪酮，其靶向宿主细胞表面上未利用的寄生虫阴离子通道，显示出优异的体外和体内ADME特性，不易获得耐药性，并表现出明确的作用机制。
Human and animal malaria parasites increase their host erythrocyte permeability to a broad range of solutes as mediated by parasite-associated ion channels. Molecular and pharmacological studies have implicated an essential role in parasite nutrient acquisition, but inhibitors suitable for development of antimalarial drugs are missing. Here, we generated a potent and specific drug lead using Plasmodium falciparum, a virulent human pathogen, and derivatives of MBX-2366, a nanomolar affinity pyridazinone inhibitor from a high-throughput screen. As this screening hit lacks the bioavailability and stability needed for in vivo efficacy, we synthesized 315 derivatives to optimize drug-like properties, establish target specificity, and retain potent activity against the parasite-induced permeability. Using a robust, iterative pipeline, we generated MBX-4055, a derivative active against divergent human parasite strains. MBX-4055 has improved oral absorption with acceptable in vivo tolerability and pharmacokinetics. It also has no activity against a battery of 35 human channels and receptors and is refractory to acquired resistance during extended in vitro selection. Single-molecule and single-cell patch-clamp indicate direct action on the plasmodial surface anion channel, a channel linked to parasite-encoded RhopH proteins. These studies identify pyridazinones as novel and tractable antimalarial scaffolds with a defined mechanism of action. SIGNIFICANCE STATEMENT: Because antimalarial drugs are prone to evolving resistance in the virulent human P. falciparum pathogen, new therapies are needed. This study has now developed a novel drug-like series of pyridazinones that target an unexploited parasite anion channel on the host cell surface, display excellent in vitro and in vivo ADME properties, are refractory to acquired resistance, and demonstrate a well defined mechanism of action.