@article{f61ad6648dd74950a1ced4487bb5d51b,
title = "Cell-impermeable staurosporine analog targets extracellular kinases to inhibit HSV and SARS-CoV-2",
abstract = "Herpes simplex virus (HSV) receptor engagement activates phospholipid scramblase triggering Akt translocation to the outer leaflet of the plasma membrane where its subsequent phosphorylation promotes viral entry. We hypothesize that this previously unrecognized outside-inside signaling pathway is employed by other viruses and that cell-impermeable kinase inhibitors could provide novel antivirals. We synthesized a cell-impermeable analog of staurosporine, CIMSS, which inhibited outer membrane HSV-induced Akt phosphorylation and blocked viral entry without inducing apoptosis. CIMSS also blocked the phosphorylation of 3-phosphoinositide dependent protein kinase 1 and phospholipase C gamma, which were both detected at the outer leaflet following HSV exposure. Moreover, vesicular stomatitis virus pseudotyped with SARS-CoV-2 spike protein (VSV-S), but not native VSV or VSV pseudotyped with Ebola virus glycoprotein, triggered this scramblase-Akt outer membrane signaling pathway. VSV-S and native SARS-CoV-2 infection were inhibited by CIMSS. Thus, CIMSS uncovered unique extracellular kinase processes linked to HSV and SARS-CoV-2 entry.",
author = "Natalia Cheshenko and Bonanno, {Jeffrey B.} and Hoffmann, {Hans Heinrich} and Jangra, {Rohit K.} and Kartik Chandran and Rice, {Charles M.} and Almo, {Steven C.} and Herold, {Betsy C.}",
note = "Funding Information: The authors thank Kartik Chandran (Albert Einstein College of Medicine, Bronx, NY) for the Huh7 cells and VSV pseudotyped viruses. The authors also thank Kelsey Vinzant for the model diagram, which was created with BioRender.com. We also thank Hillary Guzik from Analytical Imaging Facility at Albert Einstein College of Medicine for assistance with confocal laser microscope Leica SP8 (supported by small instrument grant from the NIH, IS10OD023591-01). The Bruker 600 NMR instrument was purchased with funds from NIH award 1S10OD016305. Mass spectra were recorded by the Proteomics Facility at the Albert Einstein College of Medicine. We also thank Aileen O{\textquoteright}Connell, Santa Maria Pecoraro Di Vittorio, Glen Santiago, Mary Ellen Castillo, Arnella Webson, and Sonia Shirley (Rockefeller University) for administrative or technical support. The work was also funded by NIH R01AI134367, R01 AI132633, and P30 AI124414, the G. Harold and Leila Y. Mathers Charitable Foundation and the Bawd Foundation, Fast Grants (www.fastgrants.org), a part of Emergent Ventures at the Mercatus Center, George Mason University and The Rockefeller University. Funding Information: The authors thank Kartik Chandran (Albert Einstein College of Medicine, Bronx, NY) for the Huh7 cells and VSV pseudotyped viruses. The authors also thank Kelsey Vinzant for the model diagram, which was created with BioRender.com. We also thank Hillary Guzik from Analytical Imaging Facility at Albert Einstein College of Medicine for assistance with confocal laser microscope Leica SP8 (supported by small instrument grant from the NIH, IS10OD023591-01). The Bruker 600 NMR instrument was purchased with funds from NIH award 1S10OD016305. Mass spectra were recorded by the Proteomics Facility at the Albert Einstein College of Medicine. We also thank Aileen O{\textquoteright}Connell, Santa Maria Pecoraro Di Vittorio, Glen Santiago, Mary Ellen Castillo, Arnella Webson, and Sonia Shirley (Rockefeller University) for administrative or technical support. The work was also funded by NIH R01AI134367, R01 AI132633, and P30 AI124414, the G. Harold and Leila Y. Mathers Charitable Foundation and the Bawd Foundation, Fast Grants ( www.fastgrants.org ), a part of Emergent Ventures at the Mercatus Center, George Mason University and The Rockefeller University. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s42003-022-04067-4",
language = "English (US)",
volume = "5",
journal = "Communications Biology",
issn = "2399-3642",
publisher = "Springer Nature",
number = "1",
}
