Ilaprazole and Other Novel Prazole-Based Compounds That Bind Tsg101 Inhibit Viral Budding of Herpes Simplex Virus 1 and 2 and Human Immunodeficiency Virus from Cells

In many enveloped virus families, including human immunodeficiency virus (HIV) and herpes simplex virus (HSV), a crucial, yet unexploited, step in the viral life cycle is the release of particles from the infected cell membranes. This release process is mediated by host ESCRT complex proteins, which are recruited by viral structural proteins and provide the mechanical means for membrane scission and subsequent viral budding. The prazole drug tenatoprazole was previously shown to bind to the ESCRT complex member Tsg101 and to quantitatively block the release of infectious HIV-1 from cells in culture. In this report, we show that tenatoprazole and a related prazole drug, ilaprazole, effectively block infectious HSV-1/2 release from Vero cells in culture. By electron microscopy, we found that both prazole drugs block the transit of HSV particles through the cell nuclear membrane, resulting in their accumulation in the nucleus. Ilaprazole also quantitatively blocks the release of HIV-1 from 293T cells with a 50% effective concentration (EC(50)) of 0.8 to 1.2 μM, which is much more potent than tenatoprazole. Our results indicate that prazole-based compounds may represent a class of drugs with the potential to be broad-spectrum antiviral agents against multiple enveloped viruses by interrupting the cellular Tsg101 interaction with maturing virus, thus blocking the budding process that releases particles from the cell. IMPORTANCE These results provide the basis for the development of drugs that target enveloped virus budding that can be used ultimately to control multiple virus infections in humans.