Pharmacological Elevation of Cellular Dihydrosphingomyelin Provides a Novel Antiviral Strategy against West Nile Virus Infection

The flavivirus life cycle is strictly dependent on cellular lipid metabolism. Polyphenols like gallic acid and its derivatives are promising lead compounds for new therapeutic agents as they can exert multiple pharmacological activities, including the alteration of lipid metabolism. The evaluation of our collection of polyphenols against West Nile virus (WNV), a representative medically relevant flavivirus, led to the identification of N,N'-(dodecane-1,12-diyl)bis(3,4,5-trihydroxybenzamide) and its 2,3,4-trihydroxybenzamide regioisomer as selective antivirals with low cytotoxicity and high antiviral activity (half-maximal effective concentrations [EC50s] of 2.2 and 0.24 μM, respectively, in Vero cells; EC50s of 2.2 and 1.9 μM, respectively, in SH-SY5Y cells). These polyphenols also inhibited the multiplication of other flaviviruses, namely, Usutu, dengue, and Zika viruses, exhibiting lower antiviral or negligible antiviral activity against other RNA viruses. The mechanism underlying their antiviral activity against WNV involved the alteration of sphingolipid metabolism. These compounds inhibited ceramide desaturase (Des1), promoting the accumulation of dihydrosphingomyelin (dhSM), a minor component of cellular sphingolipids with important roles in membrane properties. The addition of exogenous dhSM or Des1 blockage by using the reference inhibitor GT-11 {N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide} confirmed the involvement of this pathway in WNV infection. These results unveil the potential of novel antiviral strategies based on the modulation of the cellular levels of dhSM and Des1 activity for the control of flavivirus infection.

Bibliographic Details

Main Authors:	Jiménez de Oya, Nereida, San-Félix, Ana, Casasampere, Mireia, Blázquez, Ana B., Mingo-Casas, Patricia, Escribano-Romero, Estela, Calvo Pinilla, Eva María, Poderoso, Teresa, Casas, Josefina, Saiz Calahorra, Juan Carlos, Peréz-Pérez, María-Jesús, Martín-Acebes, M. A.
Other Authors:	Ministerio de Ciencia e Innovación (España)
Format:	artículo biblioteca
Language:	English
Published:	American Society for Microbiology 2023-04-18
Subjects:	Sphingolipid, West Nile virus, Antiviral, Antiviral agents, Flavivirus, Polyphenols, http://metadata.un.org/sdg/3, Ensure healthy lives and promote well-being for all at all ages,
Online Access:	http://hdl.handle.net/10261/307831 http://dx.doi.org/10.13039/501100004837 https://api.elsevier.com/content/abstract/scopus_id/85152973019
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