In vitro antiplasmodium effects of dermaseptin S4 derivatives
In vitro antiplasmodium effects of dermaseptin S4 derivatives
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DOI：
10.1128/aac.46.4.1059-1066.2002
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发表时间：
2002-04-01
影响因子：
4.9
通讯作者：
Ginsburg, H
中科院分区：
文献类型：
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作者：
Dagan, A;Efron, L;Ginsburg, H
13-残基皮抑菌肽S4衍生物K（4）S4（1-13）a（P）先前显示通过溶解宿主细胞杀死红细胞内疟疾寄生虫。在这项研究中，我们已经找到了能够杀死寄生虫而不溶解红细胞的肽。为了产生这样的肽，26个可变结构和大小的化合物连接到P的N末端，并在恶性疟原虫培养物中筛选抗疟原虫和溶血活性。该筛选的结果表明，无论添加剂的线性或体积如何，增加的疏水性导致放大的抗疟原虫作用。然而，增加的疏水性通常也与增加的溶血有关，除了两种衍生物：丙酰-P（C3-P）和异丁酰-P（iC 4-P）。两种酰基肽比P更有效，分别在3.8、4.3和7.7 μ M时具有50%的生长抑制。抗寄生虫作用是时间依赖性的和完全不可逆的，这意味着细胞毒性作用。还平行研究了肽抑制寄生虫生长和诱导感染和未感染红细胞溶血的能力。而感染细胞的生长抑制和溶血的剂量依赖性重叠，当细胞用P处理时，酰基肽在不引起溶血的浓度下产生50%的生长抑制。值得注意的是，酰基衍生物，但不是P，能够消散寄生虫质膜电位，并导致消耗寄生虫内钾在非溶血性条件下。这些结果清楚地表明，酰基肽可以以与宿主细胞裂解分离的方式影响寄生虫活力。总的来说，数据表明，这种策略的潜在有用性的发展选择性肽作为调查工具，并最终作为抗疟疾药物。
The 13-residue dermaseptin S4 derivative K(4)S4(1-13)a (P) was previously shown to kill intraerythrocytic malaria parasites through the lysis of the host cells. In this study, we have sought peptides that will kill the parasite without lysing the erythrocyte. To produce such peptides, 26 compounds of variable structure and size were attached to the N terminus of P and screened for antiplasmodium and hemolytic activities in cultures of Plasmodium falciparum. Results from this screen indicated that increased hydrophobicity results in amplified antiplasmodium effect, irrespective of the linearity or bulkiness of the additive. However, increased hydrophobicity also was generally associated with increased hemolysis, with the exception of two derivatives: propionyl-P (C3-P) and isobutyryl-P (iC4-P). Both acyl-peptides were more effective than P, with 50% growth inhibition at 3.8, 4.3, and 7.7 muM, respectively. The antiparasitic effect was time dependent and totally irreversible, implying a cytotoxic effect. The peptides were also investigated in parallel for their ability to inhibit parasite growth and to induce hemolysis in infected and uninfected erythrocytes. Whereas the dose dependence of growth inhibition and hemolysis of infected cells overlapped when cells were treated with P, the acyl-peptides exerted 50% growth inhibition at concentrations that did not cause hemolysis. Noticeably, the acyl derivatives, but not P, were able to dissipate the parasite plasma membrane potential and cause depletion of intraparasite potassium under nonhemolytic conditions. These results clearly demonstrate that the acyl-peptides can affect parasite viability in a manner that is dissociated from lysis of the host cell. Overall, the data indicate the potential usefulness of this strategy for development of selective peptides as investigative tools and eventually as antimalarial agents.