SARS‐CoV‐2 infection activates CREB/CBP in cellular cyclic AMP‐dependent pathways

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has caused a global coronavirus disease 2019 (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‐protein kinase (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 small interfering RNAs, 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 (EC50) 1.04 μM to Remdesivir 0.57 μM. Compared with WT virus, EC50 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.

Endogenous piRNAs Can Interact with Omicron Variant of the SARS-CoV-2 Genome

“…Each of these spiRNAs will reliably block both synthesis of the protein encoded by the spiRNAs target and gRNA replication. The effectiveness of spiRNAs is expected to be the same as in many experiments using synthetic interfering siRNA molecules [49][50][51][52][53].…”

“…Such a large value of ΔG is also associated with the length of piRNAs from 28 nt to 31 nt. These spiRNAs, fully complementary to gRNAs, are identical in function to widely used siRNAs that cause inhibition of viral RNA protein synthesis [49][50][51][52][53]. These examples demonstrate the possibility of creating drugs that suppress the reproduction of coronavirus in human cells.…”

Endogenous piRNAs Can Interact with the Omicron Variant of the SARS-CoV-2 Genome

“…Each of these spiRNAs will reliably block both the synthesis of the protein encoded by the spiRNAs target and gRNA replication. The effectiveness of spiRNAs is expected to be the same as in many experiments using synthetic interfering siRNA molecules [ 51 , 52 , 53 , 54 , 55 ].…”

“…Such large values of ΔG are also associated with the length of piRNAs from 28 nt to 31 nt. These spiRNAs, fully complementary to gRNAs, are identical in function to widely used siRNAs that cause inhibition of viral RNA protein synthesis [ 51 , 52 , 53 ]. These examples demonstrate the possibility of creating drugs that suppress the reproduction of coronavirus in human cells.…”

Integrated UPLC-MS, network pharmacology, and intestinal flora analysis to determine the treatment effect of Qiangzhi decoction on comorbid Tourette syndrome and RRTI

“…As an important second messenger, cAMP is involved in many different cellular activities, acting through cAMP-dependent effectors such as protein kinase A (PKA) and exchange proteins directly activated by cAMP ( 32 ). Yang et al ( 33 ) found that the cAMP-PKA pathway was involved in the SARS-CoV-2 infection process and induced the activation of the downstream transcription factor cAMP response element-binding protein (CREB). In studies of neuropsychiatric disorders such as TS, abnormalities in second messengers are often found.…”