Recombinant HSA-CMG2 Is a Promising Anthrax Toxin Inhibitor.
Recombinant HSA-CMG2 Is a Promising Anthrax Toxin Inhibitor.
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DOI：
10.3390/toxins8010028
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发表时间：
2016-01-20
期刊：
影响因子：
4.2
通讯作者：
Chen W
中科院分区：
文献类型：
--
作者：
Li L;Guo Q;Liu J;Zhang J;Yin Y;Dong D;Fu L;Xu J;Chen W
炭疽毒素是炭疽杆菌产生的主要毒力因子。保护性抗原（PA）是毒素的关键成分，已被确认为毒素抑制剂开发的主要靶点。抑制PA与其受体毛细血管形态发生蛋白2（CMG2）的结合可以有效阻止炭疽中毒。 CMG2 (sCMG2) 的重组、可溶性冯维勒布兰德因子 A 型 (vWA) 结构域已证明具有抗炭疽毒素的功效。然而，sCMG2体内半衰期短对其作为新型炭疽药物的开发是不利的。在本研究中，我们报道了HSA-CMG2，一种在毕赤酵母表达系统中产生的结合人血清白蛋白（HSA）和sCMG2的蛋白质，延长了sCMG2的半衰期，同时保持了PA结合能力。在体外毒素中和试验中，HSA-CMG2的IC50与sCMG2和CMG2-Fc相似，并且HSA-CMG2完全保护大鼠免受致死剂量的炭疽毒素攻击；这些相同的攻击剂量以低于当量的剂量比超过了 sCMG2，并压倒了 CMG2-Fc。我们的结果表明 HSA-CMG2 是一种有前途的炭疽毒素抑制剂，可能有助于新型炭疽药物的开发。
Anthrax toxin is the major virulence factor produced by Bacillus anthracis. Protective antigen (PA) is the key component of the toxin and has been confirmed as the main target for the development of toxin inhibitors. The inhibition of the binding of PA to its receptor, capillary morphogenesis protein-2 (CMG2), can effectively block anthrax intoxication. The recombinant, soluble von Willebrand factor type A (vWA) domain of CMG2 (sCMG2) has demonstrated potency against anthrax toxin. However, the short half-life of sCMG2 in vivo is a disadvantage for its development as a new anthrax drug. In the present study, we report that HSA-CMG2, a protein combining human serum albumin (HSA) and sCMG2, produced in the Pichia pastoris expression system prolonged the half-life of sCMG2 while maintaining PA binding ability. The IC50 of HSA-CMG2 is similar to those of sCMG2 and CMG2-Fc in in vitro toxin neutralization assays, and HSA-CMG2 completely protects rats from lethal doses of anthrax toxin challenge; these same challenge doses exceed sCMG2 at a sub-equivalent dose ratio and overwhelm CMG2-Fc. Our results suggest that HSA-CMG2 is a promising inhibitor of anthrax toxin and may contribute to the development of novel anthrax drugs.