Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway.
Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway.
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DOI：
10.1186/s13071-016-1860-3
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发表时间：
2016-11-17
影响因子：
3.2
通讯作者：
Avery VM
中科院分区：
文献类型：
--
作者：
Fletcher S;Lucantoni L;Sykes ML;Jones AJ;Holleran JP;Saliba KJ;Avery VM
在对抗疟疾的斗争中，发现具有与目前使用的药物不同的新作用模式和/或化学性质的化合物对于抵消寄生虫已知的产生耐药性的能力至关重要。另一个理想的方面是对配子体的功效，配子体是寄生虫的性发育阶段，其能够通过按蚊载体传播。使用化学救援方法，我们以前确定了靶向恶性疟原虫辅酶A（CoA）合成或利用的化合物，这是一个有前途的靶点，尚未在抗疟疾药物开发中被利用。我们报告了一系列生物学测试的结果，这些测试有助于确定物种和阶段特异性，以及这些化学上不同的化合物的潜在目标。测定化合物对恶性疟原虫配子体的活性以评估阶段特异性和降低传播的潜力。对早期配子体的IC 50值范围为60 nM-7.5 μM。除了两种化合物在所有红细胞内阶段具有亚微摩尔效力外，对晚期配子母细胞的活性较低。这些化合物都不是特异性的泛酸激酶抑制剂。CoA途径中间体的化学拯救分析表明，大多数化合物作用于两种最终的恶性疟原虫CoA合成酶，磷酸泛酰巯基乙胺腺苷酰转移酶（PPAT）或脱磷酸CoA激酶（DPCK）。最具活性的化合物靶向磷酸泛酰半胱氨酸合成酶（PPCS）或磷酸泛酰半胱氨酸脱羧酶（PPCDC）。针对克氏锥虫和布氏锥虫评价了种属特异性。对T.观察到克氏无鞭毛体;然而，三种化合物以亚微摩尔效力抑制锥鞭毛体的活力，并被证实作用于T. B.布鲁氏菌CoA合成。 利用我们先前鉴定为对无性恶性疟原虫有效的化合物，我们首次证明配子体与无性阶段一样依赖于CoA，其中两种化合物在无性形式和所有配子体阶段均表现出亚微摩尔效力。此外，三种化合物抑制T. cruzi和T. B.布氏锥鞭毛体的亚微摩尔效力，并证实对T. B.布氏杆菌CoA合成，表明CoA合成途径可能代表这些寄生虫物种中有价值的新药物靶标。本文的在线版本（doi：10.1186/s13071-016-1860-3）包含补充材料，可供授权用户使用。
In the fight against malaria, the discovery of chemical compounds with a novel mode of action and/or chemistry distinct from currently used drugs is vital to counteract the parasite’s known ability to develop drug resistance. Another desirable aspect is efficacy against gametocytes, the sexual developmental stage of the parasite which enables the transmission through Anopheles vectors. Using a chemical rescue approach, we previously identified compounds targeting Plasmodium falciparum coenzyme A (CoA) synthesis or utilization, a promising target that has not yet been exploited in anti-malarial drug development. We report on the outcomes of a series of biological tests that help to define the species- and stage-specificity, as well as the potential targets of these chemically diverse compounds. Compound activity against P. falciparum gametocytes was determined to assess stage-specificity and transmission-reducing potential. Against early stage gametocytes IC50 values ranging between 60 nM and 7.5 μM were obtained. With the exception of two compounds with sub-micromolar potencies across all intra-erythrocytic stages, activity against late stage gametocytes was lower. None of the compounds were specific pantothenate kinase inhibitors. Chemical rescue profiling with CoA pathway intermediates demonstrated that most compounds acted on either of the two final P. falciparum CoA synthesis enzymes, phosphopantetheine adenylyltransferase (PPAT) or dephospho CoA kinase (DPCK). The most active compound targeted either phosphopantothenoylcysteine synthetase (PPCS) or phosphopantothenoylcysteine decarboxylase (PPCDC). Species-specificity was evaluated against Trypanosoma cruzi and Trypanosoma brucei brucei. No specific activity against T. cruzi amastigotes was observed; however three compounds inhibited the viability of trypomastigotes with sub-micromolar potencies and were confirmed to act on T. b. brucei CoA synthesis. Utilizing the compounds we previously identified as effective against asexual P. falciparum, we demonstrate for the first time that gametocytes, like the asexual stages, depend on CoA, with two compounds exhibiting sub-micromolar potencies across asexual forms and all gametocytes stages tested. Furthermore, three compounds inhibited the viability of T. cruzi and T. b. brucei trypomastigotes with sub-micromolar potencies and were confirmed to act on T. b. brucei CoA synthesis, indicating that the CoA synthesis pathway might represent a valuable new drug target in these parasite species. The online version of this article (doi:10.1186/s13071-016-1860-3) contains supplementary material, which is available to authorized users.
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影响因子：
4
作者：
Flannery, Erika L.;McNamara, Case W.;Kim, Sang Wan;Kato, Tomoyo Sakata;Li, Fengwu;Teng, Christine H.;Gagaring, Kerstin;Manary, Micah J.;Barboa, Rachel;Meister, Stephan;Kuhen, Kelli;Vinetz, Joseph M.;Chatterjee, Arnab K.;Winzeler, Elizabeth A.
通讯作者：
Winzeler, Elizabeth A.
影响因子：
--
作者：
Huthmacher C;Hoppe A;Bulik S;Holzhütter HG
通讯作者：
Holzhütter HG
DOI：
10.3390/ph4050681
发表时间：
2011-05-01
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Grimberg BT;Mehlotra RK
通讯作者：
Mehlotra RK
影响因子：
4
作者：
Dearnley, Megan K.;Yeoman, Jeffrey A.;Dixon, Matthew W. A.
通讯作者：
Dixon, Matthew W. A.
影响因子：
4.9
作者：
Duez, Julien;Holleran, John P.;Buffet, Pierre A.
通讯作者：
Buffet, Pierre A.