Activity of lytic peptides against intracellular Trypanosoma cruzi amastigotes in vitro and parasitemias in mice
Activity of lytic peptides against intracellular Trypanosoma cruzi amastigotes in vitro and parasitemias in mice
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DOI：
10.2307/3284051
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发表时间：
1995-12-01
影响因子：
1.3
通讯作者：
Jaynes, JM
中科院分区：
文献类型：
--
作者：
Barr, SC;Rose, D;Jaynes, JM
合成了三个卵黄素样裂解肽(DC-1、DC-2和DC-2R)，在保持天然化合物的电荷分布、两亲性和疏水性的同时，几乎没有与天然化合物(天蚕素B)的序列同源性。第四个类似物(α-PI)没有这些后期性质，但分子量相似，也被合成作为非裂解肽的对照。测定了3种裂解肽的体外杀灭克氏锥虫鞭毛虫、体外细胞内无鞭毛虫的能力，以及对哺乳动物细胞系的毒性。DC-2、DC-1和DC-2R对克氏锥虫的体外杀灭效果均为100%，表明其裂解活性至少是先前试验的裂解肽类似物SB-37和Shiva-1的10倍。用低浓度(2.5 mM)的DC-1、DC-2和DC-2R单次或双次暴露于感染克氏毛滴虫的细胞中，与未处理和α-PI处理的克氏毛滴虫感染细胞相比，每细胞的无鞭毛体数量显著减少(P<；0.05)。单独用裂解肽处理的Vero细胞在数量或毒性上没有减少。其中一种多肽(DC-1)对GT小鼠的毒性和对感染克氏毛滴虫的AJ小鼠的寄生虫病的能力进行了测试。Al小鼠每天静脉注射50微克/只，连续10天未见不良反应。克氏毛滴虫感染AJ小鼠在接种后第2、4、6、8、10天给予DC-1 25 mg/只，可显著(P<；0.05)降低感染后第14天的原虫血症和死亡率(由100%降至0%)。
Three oecropin-like lytic peptides (DC-1, DC-2, and DC-2R) were synthesized with virtually no sequence homology with the natural compound (cecropin B) while retaining the charge distribution, amphipathic, and hydrophobic properties of the natural compound. A fourth analog (alpha-Pi) without these later properties, but a similar molecular weight, was also synthesized as a nonlytic peptide control. The 3 lytic peptides were examined for their ability to kill Trypanosoma cruzi trypomastigotes in vitro, intracellular amastigotes in vitro, and their toxicity to a mammalian cell line. DC-2 at 5 mu M and DC-1 and DC-2R at 10 mu M were 100% effective in killing T. cruzi trypomastigotes in vitro, suggesting at least a 10-fold increase in lytic activity over previous tested lytic peptide analogues, SB-37 and Shiva-1. When T. cruzi-infected Veto cells were treated with a single or double exposure of low concentrations (2.5 mu M) of DC-1, DC-2, and DC-2R there was a significant (P < 0.05) reduction in amastigote numbers/cell when compared to untreated and alpha-Pi-treated T. cruzi-infected cells. Vero cells alone treated with the lytic peptides showed no reduction in number or toxicity. One of the peptides (DC-1) was tested for its toxicity in GT mice and its ability to reduce parasitemias in T. cruzi-infected AJ mice. No untoward effects were seen in Al mice injected intravenously with 50 mu g/mouse daily for 10 days. There was a significant (P < 0.05) reduction in parasitemia and mortality by day 14 postinoculation(from 100% to 0%) in T. cruzi-infected AJ mice given 25 mu g of DC-1/mouse on days 2, 4, 6, 8, and 10 postinoculation.