RT Journal Article
SR Electronic
T1 Switching of OAS1 splicing isoforms mitigates SARS-CoV-2 infection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.23.457314
DO 10.1101/2021.08.23.457314
A1 Kei Iida
A1 Masahiko Ajiro
A1 Yukiko Muramoto
A1 Toru Takenaga
A1 Masatsugu Denawa
A1 Ryo Kurosawa
A1 Takeshi Noda
A1 Masatoshi Hagiwara
YR 2021
UL http://biorxiv.org/content/early/2021/08/23/2021.08.23.457314.abstract
AB Background The rapidly accumulating disease susceptibility information collected from coronavirus disease (COVID-19) patient genomes must be urgently utilized to develop therapeutic interventions for SARS-CoV-2 infection. Chromosome 12q24.13, which encodes the 2’-5’-oligoadenylate synthetase (OAS) family of proteins that sense viral genomic RNAs and trigger an antiviral response, is identified as one of the genomic regions that contains SNPs associated with COVID-19 severity. A high-risk SNP identified at the splice acceptor site of OAS1 exon 6 is known to change the proportions of the various splicing isoforms and the activity of the enzyme.Methods We employed in-silico motif search and RNA pull-down assay to define a factor responsible for the OAS1 splicing. Next, we rationally selected a candidate for slicing modulator to modulate this splicing.Results We found that inhibition of CDC-like kinase with a small chemical compound induces switching of OAS1 splice isoforms in human lung cells. In this condition, increased resistance to SARS-CoV-2 infection, enhanced RNA degradation, and transcriptional activation of interferon β1, were also observed.Conclusions The results indicate the possibility of using chemical splicing modifiers aided by genome-based precision medicine to boost the innate immune response against SARS-CoV-2 infection.Competing Interest StatementM.H. is a founder, shareholder, and member of the scientific advisory board of KinoPharma, Inc., and BTB Drug Development Research Center Co., Ltd.