Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials
Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials
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DOI：
10.1093/jac/dky008
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发表时间：
2018-05-01
影响因子：
5.2
通讯作者：
Birkholtz, Lyn-Marie
中科院分区：
文献类型：
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作者：
van der Watt, Mariette E.;Reader, Janette;Birkholtz, Lyn-Marie
目的：消灭疟疾的新化学工具应理想地针对无性寄生虫和可传播的配子体。几种咪唑并哒嗪（IMP）和2-氨基吡啶（2-AP）已被描述为靶向脂质激酶的有效抗疟候选物。然而，这些还没有被广泛探讨的阶段特异性抑制配子体恶性疟原虫寄生虫。在这里，我们提供了一个深入的评价，从这些化学型的化合物的配子体杀伤活性，并确定新的起点双重作用antimalariates.Methods：我们评估了化合物对恶性疟原虫配子体使用几个分析平台的交叉验证和严格确定的命中，进一步分析阶段特异性，行动速度和离体疗效。理化特征提取和化学基因组指纹图谱应用于探索激酶抑制敏感性profile.Results：我们确定了34个化合物对晚期配子体的亚微摩尔活性，在几个检测平台验证。其中，12种对寄生虫的选择性是哺乳动物细胞的1000倍。领跑者化合物在48小时内靶向成熟配子体并阻断向蚊子的传播。由此产生的化学基因组指纹与铅化合物处理的寄生虫揭示了针对激酶在无性寄生虫和gametocyte.Conclusions的重要性：本研究包括一个深入的评估的激酶抑制剂空间的杀配子活性。有效的先导化合物具有诱人的双重活性，并突出了在疟疾消除策略中靶向激酶超家族的重要性。
Objectives: Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) and 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these have not been extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparum parasites. Here we provide an in depth evaluation of the gametocytocidal activity of compounds from these chemotypes and identify novel starting points for dual-acting antimalarials.Methods: We evaluated compounds against P. falciparum gametocytes using several assay platforms for cross-validation and stringently identified hits that were further profiled for stage specificity, speed of action and ex vivo efficacy. Physicochemical feature extraction and chemogenomic fingerprinting were applied to explore the kinase inhibition susceptibility profile.Results: We identified 34 compounds with submicromolar activity against late stage gametocytes, validated across several assay platforms. Of these, 12 were potent at 1000-fold selectivity towards the parasite over mammalian cells. Front-runner compounds targeted mature gametocytes within 48 h and blocked transmission to mosquitoes. The resultant chemogenomic fingerprint of parasites treated with the lead compounds revealed the importance of targeting kinases in asexual parasites and gametocytes.Conclusions: This study encompasses an in-depth evaluation of the kinase inhibitor space for gametocytocidal activity. Potent lead compounds have enticing dual activities and highlight the importance of targeting the kinase superfamily in malaria elimination strategies.