Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV-2 and Exhibits Broad-Spectrum Antiviral Activity

Marie O. Pohl, Laura Martin-Sancho, Ranjala Ratnayake, Kris M. White, Laura Riva, Qi Yin Chen, Gauthier Lieber, Idoia Busnadiego, Xin Yin, Samuel Lin, Yuan Pu, Lars Pache, Romel Rosales, Marion Déjosez, Yiren Qin, Paul D. De Jesus, Anne Beall, Sunnie Yoh, Benjamin G. Hale, Thomas P. ZwakaNaoko Matsunaga, Adolfo García-Sastre, Silke Stertz, Sumit K. Chanda, Hendrik Luesch

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


There is a pressing need for host-directed therapeutics that elicit broad-spectrum antiviral activities to potentially address current and future viral pandemics. Apratoxin S4 (Apra S4) is a potent Sec61 inhibitor that prevents cotranslational translocation of secretory proteins into the endoplasmic reticulum (ER), leading to anticancer and antiangiogenic activity both in vitro and in vivo. Since Sec61 has been shown to be an essential host factor for viral proteostasis, we tested Apra S4 in cellular models of viral infection, including SARS-CoV-2, influenza A virus, and flaviviruses (Zika, West Nile, and Dengue virus). Apra S4 inhibited viral replication in a concentration-dependent manner and had high potency particularly against SARS-CoV-2 and influenza A virus, with subnanomolar activity in human cells. Characterization studies focused on SARS-CoV-2 revealed that Apra S4 impacted a post-entry stage of the viral life-cycle. Transmission electron microscopy revealed that Apra S4 blocked formation of stacked double-membrane vesicles, the sites of viral replication. Apra S4 reduced dsRNA formation and prevented viral protein production and trafficking of secretory proteins, especially the spike protein. Given the potent and broad-spectrum activity of Apra S4, further preclinical evaluation of Apra S4 and other Sec61 inhibitors as antivirals is warranted.

Original languageEnglish
Pages (from-to)1265-1279
Number of pages15
JournalACS Infectious Diseases
Issue number7
StatePublished - 8 Jul 2022


  • COVID-19
  • Sec61
  • broad-spectrum antivirals
  • double-membrane vesicles
  • host-directed therapeutics


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