Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B.

Jennifer M Reynolds, Kamal El Bissati, Jens Brandenburg, Arthur Günzl, Choukri Ben Mamoun
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引用次数: 63

Abstract

Background: The high rate of mortality due to malaria and the worldwide distribution of parasite resistance to the commonly used antimalarial drugs chloroquine and pyrimethamine emphasize the urgent need for the development of new antimalarial drugs. An alternative approach to the long and uncertain process of designing and developing new compounds is to identify among the armamentarium of drugs already approved for clinical treatment of various human diseases those that may have strong antimalarial activity.

Methods: Proteasome inhibitor bortezomib (Velcade: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid), which has been approved for treatment of patients with multiple myeloma, and a second boronate analog Z-Leu-Leu-Leu-B(OH)2 (ZL3B), were tested against four different strains of P. falciparum (3D7, HB3, W2 and Dd2) that are either sensitive or have different levels of resistance to the antimalarial drugs pyrimethamine and chloroquine.

Results: Bortezomib and ZL3B are equally effective against drug-sensitive and -resistant parasites and block intraerythrocytic development prior to DNA synthesis, but have no effect on parasite egress or invasion.

Conclusion: The identification of bortezomib and its analog as potent antimalarial drugs will set the stage for the advancement of this class of compounds, either alone or in combination therapy, for treatment of malaria, and emphasize the need for large-scale screens to identify new antimalarials within the library of clinically approved compounds.

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抗肿瘤和蛋白酶体抑制剂硼替佐米及其类似物ZL3B的抗疟活性。
背景:疟疾的高死亡率和寄生虫对常用抗疟药物氯喹和乙胺嘧啶的耐药性在世界范围内的分布表明迫切需要开发新的抗疟药物。对于设计和开发新化合物这一漫长而不确定的过程,另一种方法是在已经批准用于临床治疗各种人类疾病的药物中找出可能具有强抗疟疾活性的药物。方法:采用已获批用于治疗多发性骨髓瘤患者的蛋白酶体抑制剂硼替佐米(Velcade: [(1R)-3-甲基-1-[[(2S)-1-氧-3-苯基-2-[(吡嗪基羰基)氨基]丙基]氨基]丁基]硼酸)和第二种硼酸类似物Z-Leu-Leu-Leu-B(OH)2 (ZL3B)对4种不同的恶性疟原虫(3D7、HB3、W2和Dd2)敏感或对抗疟药物乙胺嘧啶和氯喹有不同程度的耐药)进行试验。结果:硼替佐米和ZL3B对药物敏感和耐药寄生虫同样有效,并在DNA合成之前阻断红细胞发育,但对寄生虫的出口或入侵没有影响。结论:硼替佐米及其类似物作为强效抗疟药物的鉴定将为这类化合物单独或联合治疗疟疾奠定基础,并强调需要在临床批准的化合物文库中进行大规模筛选以鉴定新的抗疟药物。
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