Drug to Genome to Drug: Discovery of New Antiplasmodial Compounds
Drug to Genome to Drug: Discovery of New Antiplasmodial Compounds
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DOI：
10.1021/jm1014617
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发表时间：
2011-05-12
影响因子：
7.3
通讯作者：
Deprez, Benoit
中科院分区：
文献类型：
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作者：
Beghyn, Terence B.;Charton, Julie;Deprez, Benoit
发现新的抗疟药物的主要策略依赖于对恶性疟原虫特定生化途径的无细胞测定。然而，似乎直接对寄生虫进行筛查是一种更有益的方法。“药物到基因组到药物”的方法包括测试一小组药物的结构类似物，这些药物作用于具有疟原虫直系同源物的人类蛋白质。人和疟原虫都具有环核苷酸磷酸二酯酶（PDE），其是细胞内稳态的关键参与者。我们合成了40种他达拉非（一种人PDE 5抑制剂）类似物，并在培养的恶性疟原虫上进行了测试，获得了有效的寄生虫生长抑制剂。我们讨论了结构-活性关系，这支持了我们的化合物通过抑制疟原虫PDE活性杀死寄生虫的假设。我们还证明，抗疟原虫衍生物抑制寄生虫的环核苷酸的水解，验证cAMP/cGMP途径作为恶性疟原虫的治疗靶点。
The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum . However, it appears that screening directly on the parasite is a more rewarding approach. The "drug to genome to drug" approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure-activity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum .