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 - Funding Information:
This research was in part supported by the NIH, National Cancer Institute Grant R01CA172310 (to H.L.), and the Debbie and Sylvia DeSantis Chair professorship (H.L.). Work in the Chanda lab was supported in part by the DoD, Grant W81XWH-20-1-0270, and the NIH/NIAID, Grant Fluomics/NOSI U19AI135972 and DHIPC Grant U19AI118610; and NCI Grant P30CA030199-40; as well as generous philanthropic donations from D. Ruch, and S. and J. Blair (to S.K.C.). This research was also partly supported by CRIPT (Center for Research for Influenza Pathogenesis and Transmission), a NIAID supported Center of Excellence for Influenza Research and Response (CEIRR, Contract # 75N93021C00014), by DARPA Grant HR0011-19-2-0020, by supplements to NIAID Grants U19AI142733, U19AI135972 and DoD Grant W81XWH-20-1-0270, and by the generous support of the JPB Foundation, the Open Philanthropy Project (Research Grant 2020-215611 (5384)), and anonymous donors to A.G-S. Work in the Stertz and Hale groups was supported by the Swiss National Science Foundation (Grant Numbers 31003A_176170 (to S.St.) and 31003A_182464 (to B.G.H.)) and imaging performed with support of the Center for Microscopy and Image Analysis, University of Zurich. We thank Sonja Fernbach for her support with the immunofluorescence quantifications using CellProfiler. The authors would like to thank Charles M. Rice (The Rockefeller University, NY) for sharing Huh-7.5 cells, Michael S. Diamond (Washington University School of Medicine in St. Louis) for the West Nile virus, Ana Fernandez-Sesma (Icahn School of Medicine at Mount Sinai) for the Dengue virus, Thomas Rogers (University of California, San Diego) for providing HeLa-hACE2 cells, Sam Wilson (University of Glasgow) for providing the A659-ACE2 cells, and Pei-Yong Shi (University of Texas Medical Branch, Galveston) for the SARS-CoV-2 clone. We thank R. Albrecht for support with the BSL-3 facility and procedures at the Icahn School of Medicine at Mount Sinai, New York.
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 -