Inhibition of coronavirus HCoV-OC43 by targeting the eIF4F complex
The translation initiation complex 4F (eIF4F) is a rate-limiting factor in protein synthesis. Alterations in eIF4F activity are linked to several diseases, including cancer and infectious diseases. To this end, coronaviruses require eIF4F complex activity to produce proteins essential for their life...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1029093/full |
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| author | Yongmei Feng Stefan Grotegut Predrag Jovanovic Valentina Gandin Steven H. Olson Rabi Murad Anne Beall Sharon Colayco Paul De-Jesus Sumit Chanda Brian P. English Robert H. Singer Michael Jackson Ivan Topisirovic Ze’ev A. Ronai |
| author_facet | Yongmei Feng Stefan Grotegut Predrag Jovanovic Valentina Gandin Steven H. Olson Rabi Murad Anne Beall Sharon Colayco Paul De-Jesus Sumit Chanda Brian P. English Robert H. Singer Michael Jackson Ivan Topisirovic Ze’ev A. Ronai |
| author_sort | Yongmei Feng |
| collection | DOAJ |
| description | The translation initiation complex 4F (eIF4F) is a rate-limiting factor in protein synthesis. Alterations in eIF4F activity are linked to several diseases, including cancer and infectious diseases. To this end, coronaviruses require eIF4F complex activity to produce proteins essential for their life cycle. Efforts to target coronaviruses by abrogating translation have been largely limited to repurposing existing eIF4F complex inhibitors. Here, we report the results of a high throughput screen to identify small molecules that disrupt eIF4F complex formation and inhibit coronavirus RNA and protein levels. Of 338,000 small molecules screened for inhibition of the eIF4F-driven, CAP-dependent translation, we identified SBI-1232 and two structurally related analogs, SBI-5844 and SBI-0498, that inhibit human coronavirus OC43 (HCoV-OC43; OC43) with minimal cell toxicity. Notably, gene expression changes after OC43 infection of Vero E6 or A549 cells were effectively reverted upon treatment with SBI-5844 or SBI-0498. Moreover, SBI-5844 or SBI-0498 treatment effectively impeded the eIF4F complex assembly, with concomitant inhibition of newly synthesized OC43 nucleocapsid protein and OC43 RNA and protein levels. Overall, we identify SBI-5844 and SBI-0498 as small molecules targeting the eIF4F complex that may limit coronavirus transcripts and proteins, thereby representing a basis for developing novel therapeutic modalities against coronaviruses. |
| format | Article |
| id | doaj-art-3f5893fb1bab4b94b39dab0daec38624 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-3f5893fb1bab4b94b39dab0daec386242024-12-19T09:07:16ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-12-011310.3389/fphar.2022.10290931029093Inhibition of coronavirus HCoV-OC43 by targeting the eIF4F complexYongmei Feng0Stefan Grotegut1Predrag Jovanovic2Valentina Gandin3Steven H. Olson4Rabi Murad5Anne Beall6Sharon Colayco7Paul De-Jesus8Sumit Chanda9Brian P. English10Robert H. Singer11Michael Jackson12Ivan Topisirovic13Ze’ev A. Ronai14Cancer Center at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesConrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesLady Davis Institute, SMBD Jewish General Hospital, Gerald Bronfman Department of Oncology and Division of Experimental Medicine, McGill University, Montreal, QC, CanadaJanelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, United StatesConrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesCancer Center at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesImmunology and Infectious Disease Center at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesImmunology and Infectious Disease Center at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesImmunology and Infectious Disease Center at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesImmunology and Infectious Disease Center at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesJanelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, United StatesJanelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, United StatesConrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesLady Davis Institute, SMBD Jewish General Hospital, Gerald Bronfman Department of Oncology and Division of Experimental Medicine, McGill University, Montreal, QC, CanadaCancer Center at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesThe translation initiation complex 4F (eIF4F) is a rate-limiting factor in protein synthesis. Alterations in eIF4F activity are linked to several diseases, including cancer and infectious diseases. To this end, coronaviruses require eIF4F complex activity to produce proteins essential for their life cycle. Efforts to target coronaviruses by abrogating translation have been largely limited to repurposing existing eIF4F complex inhibitors. Here, we report the results of a high throughput screen to identify small molecules that disrupt eIF4F complex formation and inhibit coronavirus RNA and protein levels. Of 338,000 small molecules screened for inhibition of the eIF4F-driven, CAP-dependent translation, we identified SBI-1232 and two structurally related analogs, SBI-5844 and SBI-0498, that inhibit human coronavirus OC43 (HCoV-OC43; OC43) with minimal cell toxicity. Notably, gene expression changes after OC43 infection of Vero E6 or A549 cells were effectively reverted upon treatment with SBI-5844 or SBI-0498. Moreover, SBI-5844 or SBI-0498 treatment effectively impeded the eIF4F complex assembly, with concomitant inhibition of newly synthesized OC43 nucleocapsid protein and OC43 RNA and protein levels. Overall, we identify SBI-5844 and SBI-0498 as small molecules targeting the eIF4F complex that may limit coronavirus transcripts and proteins, thereby representing a basis for developing novel therapeutic modalities against coronaviruses.https://www.frontiersin.org/articles/10.3389/fphar.2022.1029093/fullCOVID-19OC43SARS-CoV-2coronaviruseIF4Ftranslation initiation complex |
| spellingShingle | Yongmei Feng Stefan Grotegut Predrag Jovanovic Valentina Gandin Steven H. Olson Rabi Murad Anne Beall Sharon Colayco Paul De-Jesus Sumit Chanda Brian P. English Robert H. Singer Michael Jackson Ivan Topisirovic Ze’ev A. Ronai Inhibition of coronavirus HCoV-OC43 by targeting the eIF4F complex Frontiers in Pharmacology COVID-19 OC43 SARS-CoV-2 coronavirus eIF4F translation initiation complex |
| title | Inhibition of coronavirus HCoV-OC43 by targeting the eIF4F complex |
| title_full | Inhibition of coronavirus HCoV-OC43 by targeting the eIF4F complex |
| title_fullStr | Inhibition of coronavirus HCoV-OC43 by targeting the eIF4F complex |
| title_full_unstemmed | Inhibition of coronavirus HCoV-OC43 by targeting the eIF4F complex |
| title_short | Inhibition of coronavirus HCoV-OC43 by targeting the eIF4F complex |
| title_sort | inhibition of coronavirus hcov oc43 by targeting the eif4f complex |
| topic | COVID-19 OC43 SARS-CoV-2 coronavirus eIF4F translation initiation complex |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1029093/full |
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