title: Inhibition of Lassa virus glycoprotein cleavage and multicycle replication by site 1 protease-adapted alpha(1)-antitrypsin variants.
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.
  
  
  RESULTS
  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
  Our data suggest that glycoprotein cleavage by S1P is a promising target for the development of novel anti-arenaviral strategies.
authors.affiliation: Institut für Virologie, Philipps-Universität Marburg, Marburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Maisa
authors.forename: Ute
authors.initials: U
authors.lastname: Ströher
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Klenk
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Garten
authors.forename: Thomas
authors.initials: T
authors.lastname: Strecker
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D001665:Binding Sites; D016466:CHO Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D005822:Genetic Vectors; D006023:Glycoproteins / Q000378:metabolism*; D007836:Lassa virus / Q000502:physiology*; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D012697:Serine Endopeptidases; D014709:Vero Cells; D018116:Vesiculovirus / Q000235:genetics; D014759:Viral Envelope Proteins / Q000378:metabolism*; D019065:Virus Assembly / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D006023:Glycoproteins; D014759:Viral Envelope Proteins; D000515:alpha 1-Antitrypsin; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1