Derivatives of Dictyostelium differentiation-inducing factors suppress the growth of Plasmodium parasites in vitro and in vivo.
Derivatives of Dictyostelium differentiation-inducing factors suppress the growth of Plasmodium parasites in vitro and in vivo.
复制标题
盘基网柄菌分化诱导因子的衍生物可抑制体外和体内疟原虫寄生虫的生长。
DOI：
10.1016/j.bcp.2021.114834
复制
发表时间：
2021
影响因子：
5.8
通讯作者：
Kubohara Y.
中科院分区：
文献类型：
--
作者：
Mita T;Hirai M;Maki Y;Nahar S;Yoshida N;Oshima Y;Kikuchi H;Kubohara Y.
由疟原虫属原生动物引起的疟疾仍然是世界范围内的主要地方性公共卫生问题。由于青蒿素综合疗法被用作所有流行地区的一线治疗，寄生虫对这些疗法产生抗药性已成为一个严重问题。分化诱导因子1（DIF-1）是一种氯代烷基苯酮，最初发现于细胞黏菌盘基网柄菌中。DIF-1及其衍生物具有广泛的生物活性。在本研究中，我们研究了41 DIF衍生物对恶性疟原虫体外生长的影响，使用4个实验室菌株和12个现场分离株。微摩尔浓度的几种DIF衍生物强烈抑制了四种实验室菌株的生长，包括对氯喹和青蒿素表现出抗性的菌株，以及对这些药物敏感的菌株。此外，最有效的衍生物DIF-1（+2）强烈抑制12个田间分离物的生长。我们还研究了DIF-1（+2）对小鼠体内啮齿类疟疾寄生虫伯氏疟原虫（Plasmodium berghei）活性的影响。腹膜内给予DIF-1（+2）4天（50或70 mg/kg/天）可显著抑制血液中寄生虫的生长，无明显不良反应，70 mg/kg/天的剂量可显著延长动物存活期。这些结果表明，DIF衍生物，如DIF-1（+2），可以作为新的先导化合物的抗疟药的发展。
Malaria, which is caused by protozoa of the genusPlasmodium, remains a major endemic public health problem worldwide. Since artemisinin combination therapies are used as a first-line treatment in all endemic regions, the emergence of parasites resistant to these regimens has become a serious problem. Differentiation-inducing factor 1 (DIF-1) is a chlorinated alkylphenone originally found in the cellular slime mold Dictyostelium discoideum. DIF-1 and its derivatives exhibit a range of biological activities. In the present study, we investigated the effects of 41 DIF derivatives on the growth of Plasmodium falciparumin vitrousing four laboratory strains and 12 field isolates. Micromolar concentrations of several DIF derivatives strongly suppressed the growth of the four laboratory strains, including strains that exhibited resistance to chloroquine and artemisinin, as well as strains that were susceptible to these drugs. In addition, DIF-1(+2), the most potent derivative, strongly suppressed the growth of 12 field isolates. We also examined the effects of DIF-1(+2) on the activity of the rodent malarial parasite Plasmodium berghei in mice. Intraperitoneal administration of DIF-1(+2) over 4 days (50 or 70 mg/kg/day) significantly suppressed the growth of the parasite in the blood with no apparent adverse effects, and a dose of 70 mg/kg/day significantly prolonged animal survival. These results suggest that DIF derivatives, such as DIF-1(+2), could serve as new lead compounds for the development of antimalarial agents.