PNAS：阻斷瘧原蟲生長周期治療瘧疾

近日，研究人員發現一種新的手段可以通過迅速殺死>消除瘧疾感染。瘧疾每年造成高達300萬人死亡，主要感染弱勢人群，如兒童、懷孕的婦女，這種疾病在非洲、亞洲和拉丁美洲的熱帶地區常見。雖然治療這種疾病的相關藥物已經被開發出來，但瘧原蟲正在抵抗最常見的藥物，因此迫切需要新的策略來對付這種疾病。

這項新研究發現的新的潛在治療分子可以干擾寄生蟲的生長周期，利用這種效應，研究人員可以殺死瘧原蟲。在對實驗室中的樣品進行測試時，針對這一分子的樣品可在短短三個小時內殺死90％的寄生蟲。

這項研究是由倫敦帝國學院化學家和巴斯德研究所生物科學家以及法國國家科學研究中心合作完成。相關研究論文發表在>雜誌上。

研究已經發現兩種化學物質能影響瘧原蟲遺傳物質的轉錄能力，瘧原蟲的遺傳密碼將不能翻譯成蛋白質。在瘧原蟲長期棲息在血液中時，這些化合物能夠殺死寄生蟲。

科學家們希望能夠改進這些分子，提高其有效性，並證明這是一種可行的瘧疾治療策略。這項研究是由紐約巴斯德基金會和比爾及梅林達·蓋茨基金會等資助。

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms in Plasmodium falciparum.

N. A. Malmquist, T. A. Moss, S. Mecheri, A. Scherf, M. J. Fuchter.

Epigeneticfactors such as histone methylation control the developmental progression of malaria parasites during the complex life cycle in the human host. We investigated Plasmodium falciparum histone lysine methyltransferases as a potential target class for the development of novel antimalarials. We synthesized a compound library based upon a known specific inhibitor (BIX-01294) of the human G9a histone methyltransferase. Two compounds, BIX-01294 and its derivative TM2-115, inhibited P. falciparum 3D7 parasites in culture with IC50 values of ～100 nM, values at least 22-fold more potent than their apparent IC50 toward two human cell lines and one mouse cell line. These compounds irreversibly arrested parasite growth at all stages of the intraerythrocytic life cycle. Decrease in parasite viability (>40%) was seen after a 3-h incubation with 1 μM BIX-01294 and resulted in complete parasite killing after a 12-h incubation. Additionally, mice with patent Plasmodium berghei ANKA strain infection treated with a single dose (40 mg/kg) of TM2-115 had 18-fold reduced parasitemia the following day. Importantly, treatment of P. falciparum parasites in culture with BIX-01294 or TM2-115 resulted in significant reductions in histone H3K4me3 levels in a concentration-dependent and exposure time-dependent manner. Together, these results suggest that BIX-01294 and TM2-115 inhibit malaria parasite histone methyltransferases, resulting in rapid and irreversible parasite death. Our data position histone lysine methyltransferases as a previously unrecognized target class, and BIX-01294 as a promising lead compound, in a presently unexploited avenue for antimalarial drug discovery targeting multiple life-cycle stages.

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