Pentafluoro-3-hydroxy-pent-2-en-1-ones Potently Inhibit FNT-Type Lactate Transporters from all Five Human-Pathogenic Plasmodium Species.
Pentafluoro-3-hydroxy-pent-2-en-1-ones Potently Inhibit FNT-Type Lactate Transporters from all Five Human-Pathogenic Plasmodium Species.
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DOI：
10.1002/cmdc.202000952
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发表时间：
2021-04-20
期刊：
影响因子：
3.4
通讯作者：
Beitz E
中科院分区：
文献类型：
--
作者：
Walloch P;Hansen C;Priegann T;Schade D;Beitz E
原生动物寄生虫恶性疟原虫导致撒哈拉以南非洲最严重和流行的疟疾形式。以前，我们确定了疟原虫乳酸转运蛋白，PfFNT，微生物甲酸盐-亚硝酸盐转运蛋白家族的成员，作为一种新的抗疟药物靶点。利用五氟-3-羟基-β-2-烯-1-酮，我们发现了PfFNT抑制剂，其在体外有效地杀死恶性疟原虫寄生虫。 另外四种人类致病性疟原虫需要关注，即间日疟原虫，非洲以外最流行，以及区域性三日疟原虫、卵形疟原虫和诺氏疟原虫。在此，我们表明疟原虫FNT变体在蛋白质序列和功能方面高度相似。来自所有人类致病性疟原虫和啮齿动物疟疾寄生虫的FNT被五氟-3-羟基-β-2-烯-1-酮有效抑制。我们进一步建立了基于表型酵母的FNT抑制剂筛选，发现化合物对人类细胞的细胞毒性和单羧酸转运蛋白1的脱靶活性非常低，特别是最有效的FNT抑制剂BH 267.meta，使这些化合物能够进行动物模型疟疾研究。 扩张抑制：四种人类致病性疟原虫物种和啮齿动物疟疾寄生虫的FNT乳酸转运蛋白已被评估为五氟-3-羟基-β-2-烯-1-酮PfFNT抑制剂的靶标。这些蛋白质仅在外周偏离，并且同样容易受到这些有效的小分子抑制剂的影响。这些化合物表现出高的靶向效力、最小的细胞毒性和脱靶效应，使得能够转化为动物研究。
The protozoan parasite Plasmodium falciparum causes the most severe and prevailing form of malaria in sub‐Saharan Africa. Previously, we identified the plasmodial lactate transporter, PfFNT, a member of the microbial formate–nitrite transporter family, as a novel antimalarial drug target. With the pentafluoro‐3‐hydroxy‐pent‐2‐en‐1‐ones, we discovered PfFNT inhibitors that potently kill P. falciparum parasites in vitro. Four additional human‐pathogenic Plasmodium species require attention, that is, P. vivax, most prevalent outside of Africa, and the regional P. malariae, P. ovale and P. knowlesi. Herein, we show that the plasmodial FNT variants are highly similar in terms of protein sequence and functionality. The FNTs from all human‐pathogenic plasmodia and the rodent malaria parasite were efficiently inhibited by pentafluoro‐3‐hydroxy‐pent‐2‐en‐1‐ones. We further established a phenotypic yeast‐based FNT inhibitor screen, and found very low compound cytotoxicity and monocarboxylate transporter 1 off‐target activity on human cells, particularly of the most potent FNT inhibitor BH267.meta, allowing these compounds to proceed towards animal model malaria studies. Expanding inhibition: The FNT lactate transporters of four human‐pathogenic Plasmodium species and the rodent malaria parasite have been evaluated as targets of pentafluoro‐3‐hydroxy‐pent‐2‐en‐1‐one PfFNT inhibitors. The proteins deviate only in the periphery, and are similarly susceptible to these potent small‐molecule inhibitors. The compounds exhibit high on‐target potency, minimal cytotoxicity and off‐target effects enabling translation to animal studies.
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影响因子：
30.3
作者：
Gural N;Mancio-Silva L;Miller AB;Galstian A;Butty VL;Levine SS;Patrapuvich R;Desai SP;Mikolajczak SA;Kappe SHI;Fleming HE;March S;Sattabongkot J;Bhatia SN
通讯作者：
Bhatia SN
影响因子：
7.3
作者：
Walloch, Philipp;Henke, Bjoern;Beitz, Eric
通讯作者：
Beitz, Eric
影响因子：
4.4
作者：
Elbing, K;Larsson, C;Gustafsson, L
通讯作者：
Gustafsson, L
影响因子：
--
作者：
Lover, Andrew A;Dantzer, Emily;Bennett, Adam
通讯作者：
Bennett, Adam
影响因子：
4.2
作者：
Dahlin JL;Walters MA
通讯作者：
Walters MA