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PLoS Negl Trop Dis. 2009 Jun 2;3(6):e446. doi: 10.1371/journal.pntd.0000446.

Inhibition of Lassa virus glycoprotein cleavage and multicycle replication by site 1 protease-adapted alpha(1)-antitrypsin variants.

Author information

1
Institut für Virologie, Philipps-Universität Marburg, Marburg, Germany.

Abstract

BACKGROUND:

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.

PMID:
19488405
PMCID:
PMC2685025
DOI:
10.1371/journal.pntd.0000446
[Indexed for MEDLINE]
Free PMC Article

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