Amidino-rocaglates (ADRs), a class of synthetic rocaglates, are potent inhibitors of SARS-CoV-2 replication through inhibition of viral protein synthesis

• Published in: Antiviral research 2024-10, Vol.230, p.105976, Article 105976
• Main Authors: Keiser, Patrick T., Zhang, Wenhan, Ricca, Michael, Wacquiez, Alan, Grimins, Autumn, Cencic, Regina, Patten, J.J., Shah, Pranav, Padilha, Elias, Connor, John H., Pelletier, Jerry, Lyons, Shawn M., Saeed, Mohsan, Brown, Lauren E., Porco, John A., Davey, Robert A.
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Benzofurans - chemical synthesis; Benzofurans - chemistry; Benzofurans - pharmacology; Chlorocebus aethiops; COVID-19 - virology; COVID-19 Drug Treatment; Eukaryotic Initiation Factor-4A - antagonists & inhibitors; Eukaryotic Initiation Factor-4A - metabolism; Humans; Protein Biosynthesis - drug effects; SARS-CoV-2 - drug effects; Vero Cells; Viral Proteins - antagonists & inhibitors; Viral Proteins - genetics; Viral Proteins - metabolism; Virus Replication - drug effects
• ISSN: 0166-3542; 1872-9096; 1872-9096
• DOI: 10.1016/j.antiviral.2024.105976

Coronaviruses are highly transmissible respiratory viruses that cause symptoms ranging from mild congestion to severe respiratory distress. The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for new antivirals with broad-acting mechanisms to combat increasing emergence of new variants. Currently, there are only a few antivirals approved for treatment of SARS-CoV-2. Previously, the rocaglate natural product silvestrol and synthetic rocaglates such as CR-1-31b were shown to have antiviral effects by inhibiting eukaryotic translation initiation factor 4A1 (eIF4A) function and virus protein synthesis. In this study, we evaluated amidino-rocaglates (ADRs), a class of synthetic rocaglates with the most potent eIF4A-inhibitory activity to-date, for inhibition of SARS-CoV-2 infection. This class of compounds showed low nanomolar potency against multiple SARS-CoV-2 variants and in multiple cell types, including human lung-derived cells, with strong inhibition of virus over host protein synthesis and low cytotoxicity. The most potent ADRs were also shown to be active against two highly pathogenic and distantly related coronaviruses, SARS-CoV and MERS-CoV. Mechanistically, cells with mutations of eIF4A1, which are known to reduce rocaglate interaction displayed reduced ADR-associated loss of cellular function, consistent with targeting of protein synthesis. Overall, ADRs and derivatives may offer new potential treatments for SARS-CoV-2 with the goal of developing a broad-acting anti-coronavirus agent. [Display omitted] •Amidino-Rocaglates (ADRs), a class of synthetic rocaglates and eIF4A inhibitors, are potent antiviral agents.•Multiple ADRs inhibit SARS-CoV-2 infection at low nanomolar concentration in vitro while maintaining low cytotoxicity.•ADRs preferentially inhibit viral versus host translation.•Multiple SARS-CoV-2 variants of concern are strongly inhibited by the novel ADRs.