Institut für Virologie, Philipps-Universität Marburg, Marburg, Germany.
PLoS Negl Trop Dis. 2009 Jun 2;3(6):e446. doi: 10.1371/journal.pntd.0000446.
Proteolytic processing of the Lassa virus envelope glycoprotein precursor GP-C by the host proprotein convertase site 1 protease (S1P) is a prerequisite for the incorporation of the subunits GP-1 and GP-2 into viral particles and, hence, essential for infectivity and virus spread. Therefore, we tested in this study the concept of using S1P as a target to block efficient virus replication.
METHODOLOGY/PRINCIPAL FINDING: We demonstrate that stable cell lines inducibly expressing S1P-adapted alpha(1)-antitrypsin variants inhibit the proteolytic maturation of GP-C. Introduction of the S1P recognition motifs RRIL and RRLL into the reactive center loop of alpha(1)-antitrypsin resulted in abrogation of GP-C processing by endogenous S1P to a similar level observed in S1P-deficient cells. Moreover, S1P-specific alpha(1)-antitrypsins significantly inhibited replication and spread of a replication-competent recombinant vesicular stomatitis virus expressing the Lassa virus glycoprotein GP as well as authentic Lassa virus. Inhibition of viral replication correlated with the ability of the different alpha(1)-antitrypsin variants to inhibit the processing of the Lassa virus glycoprotein precursor.
CONCLUSIONS/SIGNIFICANCE: Our data suggest that glycoprotein cleavage by S1P is a promising target for the development of novel anti-arenaviral strategies.
拉沙病毒包膜糖蛋白前体 GP-C 通过宿主蛋白转化酶位点 1 蛋白酶（S1P）的蛋白水解处理是将亚基 GP-1 和 GP-2 掺入病毒颗粒的先决条件，因此对于感染性和病毒传播至关重要。因此，我们在本研究中测试了将 S1P 作为靶标以阻断有效病毒复制的概念。
方法/主要发现：我们证明，稳定表达 S1P 适应的 α1-抗胰蛋白酶变体的细胞系可抑制 GP-C 的蛋白水解成熟。将 S1P 识别基序 RRIL 和 RRLL 引入 α1-抗胰蛋白酶的反应中心环中，导致内源性 S1P 对 GP-C 的处理被阻断，达到在 S1P 缺陷细胞中观察到的相似水平。此外，S1P 特异性 α1-抗胰蛋白酶显著抑制表达拉沙病毒糖蛋白 GP 的复制型重组水疱性口炎病毒以及真实拉沙病毒的复制和传播。病毒复制的抑制与不同 α1-抗胰蛋白酶变体抑制拉沙病毒糖蛋白前体的加工能力相关。
结论/意义：我们的数据表明，糖蛋白通过 S1P 的切割是开发新型抗沙粒病毒策略的有前途的靶标。
