tetano
Editor, Senior Moderator
J Med Virol
. 2022 Dec 8.
doi: 10.1002/jmv.28383. Online ahead of print.
SARS-CoV-2 infection activates CREB/CBP in cellular cyclic AMP-dependent pathways
Qi Yang[SUP] 1 2 [/SUP], Jielin Tang[SUP] 1 2 3 [/SUP], Juan Cao[SUP] 2 [/SUP], Fengjiang Liu[SUP] 1 [/SUP], Muqing Fu[SUP] 3 [/SUP], Bao Xue[SUP] 1 2 [/SUP], Anqi Zhou[SUP] 4 [/SUP], Sijie Chen[SUP] 4 [/SUP], Junjun Liu[SUP] 1 [/SUP], Yuan Zhou[SUP] 1 2 [/SUP], Yongxia Shi[SUP] 5 [/SUP], Wei Peng[SUP] 1 6 [/SUP], Xinwen Chen[SUP] 1 2 6 [/SUP]
Affiliations
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global COVID-19 pandemic that has affected the lives of billions of individuals. However, the host-virus interactions still need further investigation to reveal the underling mechanism of SARS-CoV-2 pathogenesis. Here, transcriptomics analysis of SARS-CoV-2 infection highlighted possible correlation between host-associated signaling pathway and virus. In detail, cAMP-PKA pathway has an essential role in SARS-CoV-2 infection, followed by the interaction between cyclic AMP response element binding protein (CREB) and CREB-binding protein (CBP) could be induced and leading to the enhancement of CREB/CBP transcriptional activity. The replication of Delta and Omicron BA.5 were inhibited by about 49.4% and 44.7% after knockdown of CREB and CBP with siRNAs, respectively. Furthermore, a small organic molecule naphthol AS-E (nAS-E), which targets on the interaction between CREB and CBP, potently inhibited SARS-CoV-2 wild-type (WT) infection with comparable the half-maximal effective concentration (EC[SUB]50[/SUB] ) 1.04 μM to Remdesivir 0.57 μM. Compared with WT virus, EC[SUB]50[/SUB] in Calu-3 cells against Delta, Omicron BA.2 and Omicron BA.5 were, on average, 1.5-fold, 1.1-fold and 1.5-fold higher, respectively, nAS-E had a satisfied antiviral effect against Omicron variants. Taken together, our study demonstrated the importance of CREB/CBP induced by cAMP-PKA pathway during SARS-CoV-2 infection, and further provided a novel CREB/CBP interaction therapeutic drug targets for COVID-19. This article is protected by copyright. All rights reserved.
Keywords: CREB/CBP; SARS-CoV-2; cAMP-PKA; nAS-E.
. 2022 Dec 8.
doi: 10.1002/jmv.28383. Online ahead of print.
SARS-CoV-2 infection activates CREB/CBP in cellular cyclic AMP-dependent pathways
Qi Yang[SUP] 1 2 [/SUP], Jielin Tang[SUP] 1 2 3 [/SUP], Juan Cao[SUP] 2 [/SUP], Fengjiang Liu[SUP] 1 [/SUP], Muqing Fu[SUP] 3 [/SUP], Bao Xue[SUP] 1 2 [/SUP], Anqi Zhou[SUP] 4 [/SUP], Sijie Chen[SUP] 4 [/SUP], Junjun Liu[SUP] 1 [/SUP], Yuan Zhou[SUP] 1 2 [/SUP], Yongxia Shi[SUP] 5 [/SUP], Wei Peng[SUP] 1 6 [/SUP], Xinwen Chen[SUP] 1 2 6 [/SUP]
Affiliations
- PMID: 36477795
- DOI: 10.1002/jmv.28383
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global COVID-19 pandemic that has affected the lives of billions of individuals. However, the host-virus interactions still need further investigation to reveal the underling mechanism of SARS-CoV-2 pathogenesis. Here, transcriptomics analysis of SARS-CoV-2 infection highlighted possible correlation between host-associated signaling pathway and virus. In detail, cAMP-PKA pathway has an essential role in SARS-CoV-2 infection, followed by the interaction between cyclic AMP response element binding protein (CREB) and CREB-binding protein (CBP) could be induced and leading to the enhancement of CREB/CBP transcriptional activity. The replication of Delta and Omicron BA.5 were inhibited by about 49.4% and 44.7% after knockdown of CREB and CBP with siRNAs, respectively. Furthermore, a small organic molecule naphthol AS-E (nAS-E), which targets on the interaction between CREB and CBP, potently inhibited SARS-CoV-2 wild-type (WT) infection with comparable the half-maximal effective concentration (EC[SUB]50[/SUB] ) 1.04 μM to Remdesivir 0.57 μM. Compared with WT virus, EC[SUB]50[/SUB] in Calu-3 cells against Delta, Omicron BA.2 and Omicron BA.5 were, on average, 1.5-fold, 1.1-fold and 1.5-fold higher, respectively, nAS-E had a satisfied antiviral effect against Omicron variants. Taken together, our study demonstrated the importance of CREB/CBP induced by cAMP-PKA pathway during SARS-CoV-2 infection, and further provided a novel CREB/CBP interaction therapeutic drug targets for COVID-19. This article is protected by copyright. All rights reserved.
Keywords: CREB/CBP; SARS-CoV-2; cAMP-PKA; nAS-E.