tetano
Editor, Senior Moderator
J Virol
. 2021 Jun 9;JVI0080721.
doi: 10.1128/JVI.00807-21. Online ahead of print.
N-(4-Hydroxyphenyl) retinamide suppresses SARS-CoV-2 spike protein-mediated cell-cell fusion by a dihydroceramide Δ4-desaturase 1-independent mechanism
Yasuhiro Hayashi[SUP] 1 [/SUP], Kiyoto Tsuchiya[SUP] 2 [/SUP], Mizuki Yamamoto[SUP] 3 [/SUP], Yoko Nemoto-Sasaki[SUP] 1 [/SUP], Kazunari Tanigawa[SUP] 1 [/SUP], Kotaro Hama[SUP] 1 [/SUP], Yusuke Ueda[SUP] 1 [/SUP], Takashi Tanikawa[SUP] 4 [/SUP], Jin Gohda[SUP] 3 [/SUP], Kenji Maeda[SUP] 5 [/SUP], Jun-Ichiro Inoue[SUP] 6 [/SUP], Atsushi Yamashita[SUP] 1 [/SUP]
Affiliations
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-permeable 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, compared to that 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-meditated 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.
. 2021 Jun 9;JVI0080721.
doi: 10.1128/JVI.00807-21. Online ahead of print.
N-(4-Hydroxyphenyl) retinamide suppresses SARS-CoV-2 spike protein-mediated cell-cell fusion by a dihydroceramide Δ4-desaturase 1-independent mechanism
Yasuhiro Hayashi[SUP] 1 [/SUP], Kiyoto Tsuchiya[SUP] 2 [/SUP], Mizuki Yamamoto[SUP] 3 [/SUP], Yoko Nemoto-Sasaki[SUP] 1 [/SUP], Kazunari Tanigawa[SUP] 1 [/SUP], Kotaro Hama[SUP] 1 [/SUP], Yusuke Ueda[SUP] 1 [/SUP], Takashi Tanikawa[SUP] 4 [/SUP], Jin Gohda[SUP] 3 [/SUP], Kenji Maeda[SUP] 5 [/SUP], Jun-Ichiro Inoue[SUP] 6 [/SUP], Atsushi Yamashita[SUP] 1 [/SUP]
Affiliations
- PMID: 34106748
- DOI: 10.1128/JVI.00807-21
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-permeable 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, compared to that 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-meditated 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.