Introduction of Scaffold Nitrogen Atoms Renders Inhibitors of the Malarial L-Lactate Transporter, PfFNT, Effective against the Gly107Ser Resistance Mutation
Introduction of Scaffold Nitrogen Atoms Renders Inhibitors of the Malarial L-Lactate Transporter, PfFNT, Effective against the Gly107Ser Resistance Mutation
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DOI：
10.1021/acs.jmedchem.0c00852
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发表时间：
2020-09-10
影响因子：
7.3
通讯作者：
Beitz, Eric
中科院分区：
文献类型：
--
作者：
Walloch, Philipp;Henke, Bjoern;Beitz, Eric
疟疾寄生虫恶性疟原虫的传播对所有已知药物都具有耐药性，需要具有新作用模式的新型抑制剂。最近，我们发现并验证了疟原虫L-乳酸转运蛋白PfFNT作为一种新的抗疟药物靶点。然而，用来自疟疾盒化合物收集物MMV 007839的筛选命中物处理寄生虫，导致PfFNT Gly 107 Ser抗性突变，使抑制剂亲和力降低2个数量级。在这里，我们表明，新引入的氮原子的抑制剂支架可以作为氢键受体位点的丝氨酸羟基。亲和力的增加导致野生型PfFNT和Gly 107 Ser突变几乎相等的抑制。这项工作中最有效的抑制剂BH 267.meta以纳摩尔效力杀死培养的恶性疟原虫寄生虫，并且在体外不引起新的抗性形成。其推导的药代动力学特性似乎适合于进一步的药物开发。
The spreading of malaria parasites, Plasmodium falciparum, with resistance to all known drugs calls for novel classes of inhibitors with new modes of action. Recently, we discovered and validated the plasmodial L-lactate transporter, PfFNT, as a novel antimalarial drug target. However, treatment of parasites with a screening hit from the malaria box compound collection, MMV007839, gave rise to a PfFNT Gly107Ser resistance mutation decreasing inhibitor affinity by 2 orders of magnitude. Here, we show that newly introduced nitrogen atoms into the inhibitor scaffold can act as hydrogen bond acceptor sites to the serine hydroxyl. The gain in affinity led to almost equal inhibition of wildtype PfFNT and the Gly107Ser mutation. The most potent inhibitor of this work, BH267.meta, killed cultured P. falciparum parasites with nanomolar efficacy and did not give rise to new resistance formation in vitro. Its deduced pharmacokinetic properties appear suitable for further drug development.