p‐cymene impairs SARS‐CoV‐2 and Influenza A (H1N1) viral replication: In silico predicted interaction with SARS‐CoV‐2 nucleocapsid protein and H1N1 nucleoprotein

Panagiotopoulos, Athanasios; Tseliou, Melpomeni; Karakasiliotis, Ioannis; Kotzampasi, Danai‐Maria; Daskalakis, Vangelis; Kesesidis, Nikolaos; Notas, George; Lionis, Christos; Kampa, Marilena; Pirintsos, Stergios; Sourvinos, George; Castanas, Elias

Therapeutic regimens for the COVID‐19 pandemics remain unmet. In this line, repurposing of existing drugs against known or predicted SARS‐CoV‐2 protein actions have been advanced, while natural products have also been tested. Here, we propose that p‐cymene, a natural monoterpene, can act as a potential novel agent for the treatment of SARS‐CoV‐2‐induced COVID‐19 and other RNA‐virus‐induced diseases (influenza, rabies, Ebola). We show by extensive molecular simulations that SARS‐CoV‐2 C‐terminal structured domain contains a nuclear localization signal (NLS), like SARS‐CoV, on which p‐cymene binds with low micromolar affinity, impairing nuclear translocation of this protein and inhibiting viral replication, as verified by preliminary in vitro experiments. A similar mechanism may occur in other RNA‐viruses (influenza, rabies and Ebola), also verified in vitro for influenza, by interaction of p‐cymene with viral nucleoproteins, and structural modification of their NLS site, weakening its interaction with importin A. This common mechanism of action renders therefore p‐cymene as a possible antiviral, alone, or in combination with other agents, in a broad spectrum of RNA viruses, from SARS‐CoV‐2 to influenza A infections.