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Cell-impermeable staurosporine analog targets extracellular kinases to inhibit HSV and SARS-CoV-2.
Cheshenko, Natalia; Bonanno, Jeffrey B; Hoffmann, Hans-Heinrich; Jangra, Rohit K; Chandran, Kartik; Rice, Charles M; Almo, Steven C; Herold, Betsy C.
  • Cheshenko N; Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Bonanno JB; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Hoffmann HH; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
  • Jangra RK; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Chandran K; Department of Microbiology and Immunology, Louisiana State University Health Science Center-Shreveport, Shreveport, LA, USA.
  • Rice CM; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Almo SC; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
  • Herold BC; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
Commun Biol ; 5(1): 1096, 2022 Oct 16.
Article in English | MEDLINE | ID: covidwho-2077125
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Limits: Humans Language: English Journal: Commun Biol Year: 2022 Document Type: Article Affiliation country: S42003-022-04067-4

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Limits: Humans Language: English Journal: Commun Biol Year: 2022 Document Type: Article Affiliation country: S42003-022-04067-4