PT  - JOURNAL ARTICLE
AU  - Kei Iida
AU  - Masahiko Ajiro
AU  - Yukiko Muramoto
AU  - Toru Takenaga
AU  - Masatsugu Denawa
AU  - Ryo Kurosawa
AU  - Takeshi Noda
AU  - Masatoshi Hagiwara
TI  - Switching of OAS1 splicing isoforms mitigates SARS-CoV-2 infection
AID  - 10.1101/2021.08.23.457314
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.08.23.457314
4099  - http://biorxiv.org/content/early/2021/08/23/2021.08.23.457314.short
4100  - http://biorxiv.org/content/early/2021/08/23/2021.08.23.457314.full
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.