Proteomics

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Receptor Tyrosine Kinase Inhibitors Block proliferation of coronavirus mainly through p38 mitogen-activated protein kinase pathways


ABSTRACT: Emerging coronaviruses (CoVs) primarily cause severe gastroenteric or respiratory diseases in humans and animals, for which no approved therapeutics are available so far. Here A9, a receptor tyrosine kinase inhibitors (RTKIs) of the tyrphostin class was identified as a robust inhibitor of TGEV (Transmissible gastroenteritis virus) infection in cell-based assays. Time-of-addition studies suggested that A9 mainly acts at post-adsorption stage of the TGEV life cycle. Moreover, it also exhibited potent antiviral activity against various coronavirus replication, including MHV, PEDV and FIPV. We further investigated the mechanism of action of A9 against TGEV infection in vitro with comparative phosphoproteomics analysis. We specifically identified the A9 target, p38 and JNK1, the downstream molecules of receptor tyrosine kinases (RTKs) as required for efficient TGEV replication in vitro through plaque assay, qRT-PCR and western blotting assays. Additionally, tests of p38 and JNK1 inhibitors also indicated that interventions targeting p38 was more effective in suppressing TGEV propagation than the JNK. In conclusion, these findings indicate that the receptor tyrosine kinase inhibitor A9 can directly inhibits TGEV replication and its inhibitory activity on TGEV replication mainly regulated by targeting p38, which provide vital clues to design novel drugs against coronavirus.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Sus Scrofa (pig)

TISSUE(S): Cell Culture

SUBMITTER: xiaomei li  

LAB HEAD: guiqing peng

PROVIDER: PXD010685 | Pride | 2020-05-26

REPOSITORIES: Pride

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Publications

Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways.

Dong Wanyu W   Xie Wenting W   Liu Yunbo Y   Sui Baokun B   Zhang Hao H   Liu Liran L   Tan Yubei Y   Tong Xiaohan X   Fu Zhen F ZF   Yin Ping P   Fang Liurong L   Peng Guiqing G  

Antiviral research 20191118


Emerging coronaviruses (CoVs) primarily cause severe gastroenteric or respiratory diseases in humans and animals, and no approved therapeutics are currently available. Here, A9, a receptor tyrosine kinase inhibitor (RTKI) of the tyrphostin class, is identified as a robust inhibitor of transmissible gastroenteritis virus (TGEV) infection in cell-based assays. Moreover, A9 exhibited potent antiviral activity against the replication of various CoVs, including murine hepatitis virus (MHV), porcine e  ...[more]

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