A protein-based therapeutic for human cytomegalovirus infection
A protein-based therapeutic for human cytomegalovirus infection
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DOI：
10.1073/pnas.050504297
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发表时间：
2000-03-14
影响因子：
11.1
通讯作者：
Thomas, G
中科院分区：
文献类型：
--
作者：
Jean, F;Thomas, L;Thomas, G
目前的抗病毒策略是针对病毒基因产物。虽然最初取得了成功，但它们的严重毒性和容易被产生耐药变异所绕过，限制了它们的用途。相比之下，宿主细胞丝氨酸内源性蛋白酶furin在许多病原体的蛋白水解激活中的核心作用表明内源性蛋白酶是治疗的战略靶点。在此，我们表明，通过外源性添加生物工程蛇形蛋白α (1)-PDX，传染性人巨细胞病毒的产生显著减少。该蛋白是一种有效的选择性呋喃抑制剂（K-i = 0.6 nM），在细胞培养模型中比目前使用的抗疱疹药物有效10倍。许多致病病毒的包膜糖蛋白的加工和几种细菌毒素的激活都需要呋喃，这表明呋喃的选择性抑制剂具有广泛抗病原体的潜力。
Current antiviral strategies target viral gene products. Although initially successful, their severe toxicity and susceptibility to circumvention by the generation of drug-resistant variants limit their usefulness. By contrast, the central role of the host cell serine endoprotease furin in the proteolytic activation of numerous pathogens points to the endoprotease as a strategic target for therapeutics. Herein, we show that the production of infectious human cytomegalovirus is dramatically reduced by exogenous addition of a bioengineered serpin, alpha(1)-PDX. This protein is a potent and selective furin inhibitor (K-i = 0.6 nM) and is 10-fold more effective than currently used antiherpetic agents in cell-culture models. The requirement of furin for the processing of envelope glycoproteins from many pathogenic viruses and for the activation of several bacterial toxins suggests that selective inhibitors of furin have potential as broad-based anti-pathogens.