title: Peptide mimetics of gamma interferon possess antiviral properties against vaccinia virus and other viruses in the presence of poxvirus B8R protein.
abstract: We have developed peptide mimetics of gamma interferon (IFN-gamma) that play a direct role in the activation and nuclear translocation of STAT1alpha transcription factor. These mimetics do not act through recognition by the extracellular domain of IFN-gamma receptor but rather bind to the cytoplasmic domain of the receptor chain 1, IFNGR-1, and thereby initiate the cellular signaling. Thus, we hypothesized that these mimetics would bypass the poxvirus virulence factor B8R protein that binds to intact IFN-gamma and prevents its interaction with the receptor. Human and murine IFN-gamma mimetic peptides were introduced into an adenoviral vector for intracellular expression. Murine IFN-gamma mimetic peptide was also expressed via chemical synthesis with an attached lipophilic group for penetration of cell plasma membrane. In contrast to intact human IFN-gamma, the mimetics did not bind poxvirus B8R protein, a homolog of the IFN-gamma receptor extracellular domain. Expression of B8R protein in WISH cells did not block the antiviral effect of the mimetics against encephalomyocarditis or vesicular stomatitis virus, while the antiviral activity of human IFN-gamma was neutralized. Consistent with the antiviral activity, the upregulation of MHC class I molecules on WISH cells by the IFN-gamma mimetics was not affected by B8R protein, while IFN-gamma-induced upregulation was blocked. Finally, the mimetics, but not IFN-gamma, inhibited vaccinia virus replication in African green monkey kidney BSC-40 cells. The data presented demonstrate that small peptide mimetics of IFN-gamma can avoid the B8R virulence factor for poxviruses and, thus, are potential candidates for antivirals against smallpox virus.
authors.affiliation: University of Florida, Department of Microbiology and Cell Science, Building 981, Room 1052, P.O. Box 110700, Gainesville, FL 32611-0700, USA. ahmed1@ufl.edu
authors.forename: Chulbul M I
authors.initials: CM
authors.lastname: Ahmed
authors.forename: Marjorie A
authors.initials: MA
authors.lastname: Burkhart
authors.forename: Prem S
authors.initials: PS
authors.lastname: Subramaniam
authors.forename: Mustafa G
authors.initials: MG
authors.lastname: Mujtaba
authors.forename: Howard M
authors.initials: HM
authors.lastname: Johnson
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology; D032701:Biomimetics; D002460:Cell Line; D004686:Encephalomyocarditis virus / Q000187:drug effects* / Q000378:metabolism*; D005822:Genetic Vectors; D006801:Humans; D007371:Interferon-gamma / Q000138:chemical synthesis / Q000235:genetics / Q000494:pharmacology*; D014616:Vaccinia virus / Q000187:drug effects* / Q000378:metabolism*; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects* / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D037521:Virulence Factors; D007371:Interferon-gamma