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首页> 外文期刊>Bioorganic and Medicinal Chemistry >Inhibition of S. aureus α-hemolysin and B. anthracis lethal toxin by β-cyclodextrin derivatives
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Inhibition of S. aureus α-hemolysin and B. anthracis lethal toxin by β-cyclodextrin derivatives

机译：β-环糊精衍生物对金黄色葡萄球菌α-溶血素和炭疽芽孢杆菌致死毒素的抑制作用

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Many pathogens utilize the formation of transmembrane pores in target cells in the process of infection. A great number of pore-forming proteins, both bacterial and viral, are considered to be important virulence factors, which makes them attractive targets for the discovery of new therapeutic agents. Our research is based on the idea that compounds designed to block the pores can inhibit the action of virulence factors, and that the chances to find high affinity blocking agents increase if they have the same symmetry as the target pore. Recently, we demonstrated that derivatives of β-cyclodextrin inhibited anthrax lethal toxin (LeTx) action by blocking the transmembrane pore formed by the protective antigen (PA) subunit of the toxin. To test the broader applicability of this approach, we sought β-cyclodextrin derivatives capable of inhibiting the activity of Staphylococcus aureus α-hemolysin (α-HL), which is regarded as a major virulence factor playing an important role in staphylococcal infection. We identified several amino acid derivatives of β-cyclodextrin that inhibited the activity of α-HL and LeTx in cell-based assays at low micromolar concentrations. One of the compounds was tested for the ability to block ion conductance through the pores formed by α-HL and PA in artificial lipid membranes. We anticipate that this approach can serve as the basis for a structure-directed drug discovery program to find new and effective therapeutics against various pathogens that utilize pore-forming proteins as virulence factors.
机译：许多病原体在感染过程中利用靶细胞中跨膜孔的形成。大量的细菌和病毒致孔蛋白被认为是重要的毒力因子，这使其成为发现新治疗剂的有吸引力的靶标。我们的研究基于这样的思想：设计用于封闭孔的化合物可以抑制毒力因子的作用，并且如果它们与目标孔具有相同的对称性，则发现高亲和力封闭剂的机会就会增加。最近，我们证明了β-环糊精衍生物可通过阻断毒素的保护性抗原（PA）亚基形成的跨膜孔来抑制炭疽致死毒素（LeTx）的作用。为了测试该方法的广泛适用性，我们寻求了能够抑制金黄色葡萄球菌α-溶血素（α-HL）活性的β-环糊精衍生物，后者被认为是在葡萄球菌感染中起重要作用的主要毒力因子。我们在低微摩尔浓度的基于细胞的测定中鉴定了几种β-环糊精的氨基酸衍生物，它们可抑制α-HL和LeTx的活性。测试了其中一种化合物在人造脂质膜中阻断离子传导通过α-HL和PA形成的孔的能力。我们期望这种方法可以作为结构导向药物发现计划的基础，以寻找针对利用孔形成蛋白作为致病因子的各种病原体的新型有效疗法。

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