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N-(4-Hydroxyphenyl) Retinamide Suppresses SARS-CoV-2 Spike Protein-Mediated Cell-Cell Fusion by a Dihydroceramide Δ4-Desaturase 1-Independent Mechanism.
Hayashi, Yasuhiro; Tsuchiya, Kiyoto; Yamamoto, Mizuki; Nemoto-Sasaki, Yoko; Tanigawa, Kazunari; Hama, Kotaro; Ueda, Yusuke; Tanikawa, Takashi; Gohda, Jin; Maeda, Kenji; Inoue, Jun-Ichiro; Yamashita, Atsushi.
  • Hayashi Y; Faculty of Pharma-Science, Teikyo Universitygrid.264706.1, Tokyo, Japan.
  • Tsuchiya K; AIDS Clinical Center, National Center for Global Health and Medicine Hospital, Tokyo, Japan.
  • Yamamoto M; Research Center for Asian Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • Nemoto-Sasaki Y; Faculty of Pharma-Science, Teikyo Universitygrid.264706.1, Tokyo, Japan.
  • Tanigawa K; Faculty of Pharma-Science, Teikyo Universitygrid.264706.1, Tokyo, Japan.
  • Hama K; Faculty of Pharma-Science, Teikyo Universitygrid.264706.1, Tokyo, Japan.
  • Ueda Y; Faculty of Pharma-Science, Teikyo Universitygrid.264706.1, Tokyo, Japan.
  • Tanikawa T; Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama, Japan.
  • Gohda J; Research Center for Asian Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • Maeda K; Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • Inoue JI; Senior Professor Office, The University of Tokyo, Tokyo, Japan.
  • Yamashita A; Faculty of Pharma-Science, Teikyo Universitygrid.264706.1, Tokyo, Japan.
J Virol ; 95(17): e0080721, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1486516
ABSTRACT
The membrane fusion between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and host cells is essential for the initial step of infection; therefore, the host cell membrane components, including sphingolipids, influence the viral infection. We assessed several inhibitors of the enzymes pertaining to sphingolipid metabolism, against SARS-CoV-2 spike protein (S)-mediated cell-cell fusion and viral infection. N-(4-Hydroxyphenyl) retinamide (4-HPR), an inhibitor of dihydroceramide Δ4-desaturase 1 (DES1), suppressed cell-cell fusion and viral infection. The analysis of sphingolipid levels revealed that the inhibition efficiencies of cell-cell fusion and viral infection in 4-HPR-treated cells were consistent with an increased ratio of saturated sphinganine-based lipids to total sphingolipids. We investigated the relationship of DES1 with the inhibition efficiencies of cell-cell fusion. The changes in the sphingolipid profile induced by 4-HPR were mitigated by the supplementation with exogenous cell-permeative ceramide; however, the reduced cell-cell fusion could not be reversed. The efficiency of cell-cell fusion in DES1 knockout (KO) cells was at a level comparable to that in wild-type (WT) cells; however, the ratio of saturated sphinganine-based lipids to the total sphingolipids was higher in DES1 KO cells than in WT cells. 4-HPR reduced cell membrane fluidity without any significant effects on the expression or localization of angiotensin-converting enzyme 2, the SARS-CoV-2 receptor. Therefore, 4-HPR suppresses SARS-CoV-2 S-mediated membrane fusion through a DES1-independent mechanism, and this decrease in membrane fluidity induced by 4-HPR could be the major cause for the inhibition of SARS-CoV-2 infection. IMPORTANCE Sphingolipids could play an important role in SARS-CoV-2 S-mediated membrane fusion with host cells. We studied the cell-cell fusion using SARS-CoV-2 S-expressing cells and sphingolipid-manipulated target cells, with an inhibitor of the sphingolipid metabolism. 4-HPR (also known as fenretinide) is an inhibitor of DES1, and it exhibits antitumor activity and suppresses cell-cell fusion and viral infection. 4-HPR suppresses membrane fusion through a decrease in membrane fluidity, which could possibly be the cause for the inhibition of SARS-CoV-2 infection. There is accumulating clinical data on the safety of 4-HPR. Therefore, it could be a potential candidate drug against COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Oxidoreductases / Cell Membrane / Fenretinide / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / Membrane Fluidity Type of study: Prognostic study Limits: Humans Language: English Journal: J Virol Year: 2021 Document Type: Article Affiliation country: Jvi.00807-21

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Oxidoreductases / Cell Membrane / Fenretinide / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / Membrane Fluidity Type of study: Prognostic study Limits: Humans Language: English Journal: J Virol Year: 2021 Document Type: Article Affiliation country: Jvi.00807-21