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.

The Fundación General CSIC (FGCSIC) launches the fourth edition of its ComFuturo programme: ComFuturo iAGE, a postdoctoral initiative co-financed by the Marie Skłodowska-Curie Actions COFUND scheme of...

Deep mutational scanning (DMS) can define functional constraints acting on viral proteomes by quantifying the effects of mutations on viral fitness. However, DMS analyses do not discern type-specific ...

Communications Biology - Identification of safe and effective broad-spectrum antivirals based on modified chitosan sulfate derivatives.

Enteroviruses dramatically remodel the cellular infrastructure for efficient replication and curtailing host antiviral responses. Proteases 2Apro and 3Cpro have been implicated in these processes base...

Scientific Reports - An efficient plasmid-based system for the recovery of recombinant vesicular stomatitis virus encoding foreign glycoproteins