Omicron sublineages of SARS-CoV-2 have accelerated the spread of the virus and facilitated immune escape. In this work, we demonstrate that compound 2, a potent HIV and enterovirus A71 (EV-A71) entry inhibitor previously discovered in our research group, also displays potent in vitro activity against different SARS-CoV-2 Omicron variants while showing no activity against the ancestral SARS-CoV-2 Wuhan strain. Moreover, its sodium salt (2-Na salt) exhibited in vivo antiviral activity in a murine model of Omicron BA.1. infection. Indeed, biophysical and cryo-EM studies revealed binding of 2-Na salt to the Omicron BA.1 spike (S) protein stabilizing a “closed” form in which ∼75% of the S particles have all RBDs down, unlike the usual “open” form with one RBD up. Such “closed” form decreases S avidity for the cellular receptor ACE2, thus inhibiting viral entry. Computer-assisted modeling studies strongly suggest that 2 can interact with the intersubunit cavity of the S trimer of the Omicron BA.1 subvariant, making use of the multivalency principle. In this context, compound 2 can be considered a pharmacological tool for studying and validating new antiviral strategies against Omicron variants. We also identified 2 as a potent inhibitor of RSV and the Ebola virus. The effectiveness of 2 against a diverse set of viruses of different families supports its use as a promising lead for the development of entry inhibitors against current and future viral infections, representing a meaningful advance in the field.

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