TY - JOUR
T1 - Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV-2 and Exhibits Broad-Spectrum Antiviral Activity
AU - Pohl, Marie O.
AU - Martin-Sancho, Laura
AU - Ratnayake, Ranjala
AU - White, Kris M.
AU - Riva, Laura
AU - Chen, Qi Yin
AU - Lieber, Gauthier
AU - Busnadiego, Idoia
AU - Yin, Xin
AU - Lin, Samuel
AU - Pu, Yuan
AU - Pache, Lars
AU - Rosales, Romel
AU - Déjosez, Marion
AU - Qin, Yiren
AU - De Jesus, Paul D.
AU - Beall, Anne
AU - Yoh, Sunnie
AU - Hale, Benjamin G.
AU - Zwaka, Thomas P.
AU - Matsunaga, Naoko
AU - García-Sastre, Adolfo
AU - Stertz, Silke
AU - Chanda, Sumit K.
AU - Luesch, Hendrik
N1 - Publisher Copyright:
© 2022 The Authors. Published by American Chemical Society.
PY - 2022/7/8
Y1 - 2022/7/8
N2 - 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.
AB - 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.
KW - COVID-19
KW - Sec61
KW - broad-spectrum antivirals
KW - double-membrane vesicles
KW - host-directed therapeutics
UR - http://www.scopus.com/inward/record.url?scp=85134360803&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.2c00008
DO - 10.1021/acsinfecdis.2c00008
M3 - Article
C2 - 35766385
AN - SCOPUS:85134360803
SN - 2373-8227
VL - 8
SP - 1265
EP - 1279
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 7
ER -