Research ArticlesMedicine

An off-target effect of BX795 blocks herpes simplex virus type 1 infection of the eye

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Science Translational Medicine  14 Feb 2018:
Vol. 10, Issue 428, eaan5861
DOI: 10.1126/scitranslmed.aan5861

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Herpes tanked by a kinase inhibitor

Interferon (IFN) responses are a cornerstone of antiviral immunity. As TANK-binding kinase 1 (TBK1) promotes IFN, Jaishankar et al. thought that using the TBK1 inhibitor BX795 would allow for increased herpes virus replication. Somewhat surprisingly, they found that this inhibitor reduced replication and may be a promising antiviral candidate. They tested BX795 in different herpes simplex virus type 1 (HSV-1) ocular infection models and examined the pathway through which it was working, which was not TBK1. BX795 may have advantages over traditional nucleoside analogs currently used to combat herpes infections and should be investigated further.

Abstract

Herpes simplex virus type 1 (HSV-1) causes recurrent mucocutaneous lesions in the eye that may advance to corneal blindness. Nucleoside analogs exemplified by acyclovir (ACV) form the primary class of antiherpetic drugs, but this class suffers limitations due to the emergence of viral resistance and other side effects. While studying the molecular basis of ocular HSV-1 infection, we observed that BX795, a commonly used inhibitor of TANK-binding kinase 1 (TBK1), strongly suppressed infection by multiple strains of HSV-1 in transformed and primary human cells, cultured human and animal corneas, and a murine model of ocular infection. Our investigations revealed that the antiviral activity of BX795 relies on targeting Akt phosphorylation in infected cells, leading to the blockage of viral protein synthesis. This small-molecule inhibitor, which was also effective against an ACV-resistant HSV-1 strain, shows promise as an alternative to existing drugs and as an effective topical therapy for ocular herpes infection. Collectively, our results obtained using multiple infection models and virus strains establish BX795 as a promising lead compound for broad-spectrum antiviral applications in humans.

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