ANTIMALARIAL ACTIVITY OF A 4',5'-UNSATURATED 5'-FLUOROADENOSINE MECHANISM-BASED INHIBITOR OF S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE
ANTIMALARIAL ACTIVITY OF A 4',5'-UNSATURATED 5'-FLUOROADENOSINE MECHANISM-BASED INHIBITOR OF S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE
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DOI：
10.1016/0006-2952(90)90562-y
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发表时间：
1990-08-01
影响因子：
5.8
通讯作者：
MCCANN, PP
中科院分区：
文献类型：
--
作者：
BITONTI, AJ;BAUMANN, RJ;MCCANN, PP
一种S-腺苷-L-高半胱氨酸水解酶（SAH水解酶; EC 3.3.1.1.）的4“，5”-不饱和5“-氟腺苷抑制剂，MDL 28842对体外恶性疟原虫和小鼠伯氏疟原虫均有明显的抑制作用。对伯氏疟原虫生长的抑制与用MDL 28842处理的小鼠红细胞中S-腺苷-L-高半胱氨酸（SAH）浓度的大幅增加有关。SAH的增加显然是由于小鼠红细胞SAH水解酶活性的抑制，因为从感染的红细胞分离的伯氏疟原虫或恶性疟原虫中均检测不到SAH水解酶活性，尽管在小鼠红细胞提取物中很容易检测到酶活性。因此，MDL 28842可能通过不利地改变宿主红细胞的环境而间接地抑制疟原虫生长。SAH水解酶代表了一个有价值的目标，为未来发展的有效抑制剂的化疗疟疾。
A 4'',5''-unsaturated 5''-fluoroadenosine inhibitor of S-adenosyl-L-homocysteine hydrolase (SAH hydrolase; EC 3.3.1.1.), MDL 28842, was found to inhibit markedly the growth of Plasmodium falciparum in vitro and Plasmodium berghei in mice. Inhibition of P. berghei growth was associated with a large increase in the concentration of S-adenosyl-L-homocysteine (SAH) in the erythrocytes of mice treated with MDL 28842. This increase in SAH was due apparently to inhibition of the mouse erythrocyte SAH hydrolase activity, because SAH hydrolase activity was undetectable in either P. berghei or P. falciparum isolated from infected erythrocytes, although enzyme activity was readily detected in mouse erythrocyte extracts. Therefore, MDL 28842 probably inhibits plasmodial growth indirectly by adversely changing the milieu of the host erythrocyte. SAH hydrolase represents a worthwhile target for the future development of potent inhibitors for the chemotherapy of malaria.