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3CL-Pro is the SARS-CoV-2 main protease (MPro). It acts as a homodimer to cleave the large polyprotein 1ab transcript into proteins that are necessary for viral growth and replication. 3CL-Pro has been one of the most studied SARS-CoV-2 proteins and a main target of therapeutics. A number of drug candidates have been reported, including natural products. Here, we employ elaborate computational methods to explore the dimerization of the 3CL-Pro protein, and we formulate a computational context to identify potential inhibitors of this process. We report that fortunellin (acacetin 7-O-neohesperidoside), a natural flavonoid O-glycoside, and its structural analogs are potent inhibitors of 3CL-Pro dimerization, inhibiting viral plaque formation in vitro. We thus propose a novel basis for the search of pharmaceuticals as well as dietary supplements in the fight against SARS-CoV-2 and COVID-19.

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., Left panel: Docking of p‐cymene within the NLS sequence of N protein, shown in yellow. The ligand interacts preferentially with Arginine 262 and Threonine 265, in the center of the NLS sequence (aa 258–268), therefore impairing the interaction of N with importin‐α. Right panel: p‐cymene inhibits (black curve) and prevents (red curve) SARS‐CoV‐2 replication, in a dose‐dependent manner.