Bachran Christopher, Leppla Stephen H
BioMed X Innovation Center, Heidelberg 69120, Germany.
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Toxins (Basel). 2016 Jul 1;8(7):197. doi: 10.3390/toxins8070197.
Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery.
炭疽毒素是一种来自炭疽芽孢杆菌的强效三聚体蛋白毒素。它是两种毒力因子之一，可引发炭疽病。该毒素的受体结合成分——保护性抗原，需要被类弗林蛋白酶切割才能激活，并将酶部分致死因子和水肿因子递送至细胞胞质溶胶中。蛋白酶切割位点的改变可使毒素在肿瘤相关蛋白酶存在时选择性激活。将炭疽毒素重新靶向肿瘤细胞的这一最初想法在近年来得到了进一步完善，并促成了许多炭疽毒素变体的设计，这些变体在动物模型中实现了成功的肿瘤治疗。这些变体包括不同毒素变体的组合，这些变体需要由两种不同的肿瘤相关蛋白酶激活，以提高毒素激活的特异性。炭疽毒素系统已被证明是一种将多种酶部分递送至细胞内的通用系统。最近，通过将泛素作为胞质切割位点引入致死因子融合蛋白中，对这种高效递送系统进行了进一步改良。这篇综述文章描述了该肿瘤靶向和药物递送领域的最新进展。
