Abstract
We have developed peptide mimetics of gamma interferon (IFN-γ) that play a direct role in the activation and nuclear translocation of STAT1α transcription factor. These mimetics do not act through recognition by the extracellular domain of IFN-γ 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-γ and prevents its interaction with the receptor. Human and murine IFN-γ mimetic peptides were introduced into an adenoviral vector for intracellular expression. Murine IFN-γ 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-γ, the mimetics did not bind poxvirus B8R protein, a homolog of the IFN-γ 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-γ was neutralized. Consistent with the antiviral activity, the upregulation of MHC class I molecules on WISH cells by the IFN-γ mimetics was not affected by B8R protein, while IFN-γ-induced upregulation was blocked. Finally, the mimetics, but not IFN-γ, inhibited vaccinia virus replication in African green monkey kidney BSC-40 cells. The data presented demonstrate that small peptide mimetics of IFN-γ can avoid the B8R virulence factor for poxviruses and, thus, are potential candidates for antivirals against smallpox virus.
