Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens
Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens
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DOI：
10.1074/jbc.m703847200
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发表时间：
2007-07-20
影响因子：
4.8
通讯作者：
Strongin, Alex Y.
中科院分区：
文献类型：
--
作者：
Shiryaev, Sergey A.;Remacle, Albert G.;Strongin, Alex Y.
病原体或其毒素，包括流感病毒、假单胞菌和炭疽毒素，需要宿主前蛋白转化酶（PC）的加工才能进入宿主细胞并引起疾病。相反，抑制PC可能会保护宿主细胞免受多种弗林蛋白酶依赖性，但在其他方面无关的病原体。为了确定这一概念是否正确，我们设计了特定的纳摩尔抑制剂的PC模拟从延长切割基序TPQRERRKKR向下箭头GL的禽流感H5 N1血凝素。然后，我们证实了抑制肽在体外对荧光肽，炭疽保护性抗原（PA 83），和流感血凝素底物的效力，也在小鼠体内对两个不相关的毒素，炭疽和假单胞菌外毒素。在P1'处具有Phe/Tyr的肽对弗林蛋白酶具有更高的选择性。具有P1' Thr的肽对多种PC是有效的。我们的策略是将肽序列建立在禽流感病毒已知的弗林蛋白酶切割基序上，这显示了用已知底物开始抑制剂设计的能力。我们的研究结果证实，抑制弗林蛋白酶样PC保护宿主免受不同的弗林蛋白酶依赖性感染，并为针对急性疾病的新型宿主细胞治疗奠定了基础。
Pathogens or their toxins, including influenza virus, Pseudomonas, and anthrax toxins, require processing by host proprotein convertases (PCs) to enter host cells and to cause disease. Conversely, inhibiting PCs is likely to protect host cells from multiple furin-dependent, but otherwise unrelated, pathogens. To determine if this concept is correct, we designed specific nanomolar inhibitors of PCs modeled from the extended cleavage motif TPQRERRRKKR down arrow GL of the avian influenza H5N1 hemagglutinin. We then confirmed the efficacy of the inhibitory peptides in vitro against the fluorescent peptide, anthrax protective antigen (PA83), and influenza hemagglutinin substrates and also in mice in vivo against two unrelated toxins, anthrax and Pseudomonas exotoxin. Peptides with Phe/Tyr at P1' were more selective for furin. Peptides with P1' Thr were potent against multiple PCs. Our strategy of basing the peptide sequence on a furin cleavage motif known for an avian flu virus shows the power of starting inhibitor design with a known substrate. Our results confirm that inhibiting furin-like PCs protects the host from the distinct furin-dependent infections and lay a foundation for novel, host cell-focused therapies against acute diseases.