Potent and Selective Knockdown of Tyrosine Kinase 2 by Antisense Oligonucleotides

Abstract Tyrosine kinase 2 (TYK2) is a member of the JAK family nonreceptor tyrosine kinase, together with JAK1, JAK2, and JAK3. JAKs are important signaling mediators many proinflammatory cytokines represent compelling pharmacological targets for autoimmune inflammatory diseases. Pan-acting small-molecule inhibitors were approved treatment rheumatoid arthritis ulcerative colitis. However, their limited selectivity among members have led to undesirable side effects, driving search toward specific inhibitors. Recently, TYK2 has emerged as target choice diseases severe COVID-19 an optimum balance between efficacy safety, based on observations from human genetics studies clinical outcomes several agents targeting cytokine pathways which plays essential role. In this article, we address selective genetic sequence space through development antisense oligonucleotides (ASOs) against mRNA. Potent ASO candidates identified screening over 200 ASOs using locked nucleic acid gapmer design. The lead exhibited potent knockdown mRNA protein across panel model cell lines in dose-dependent manner, showing no reduction expression levels other paralogs. agreement depletion proteins, TYK2-mediated pathways, including IFN-α IL-12, inhibited upon treatment. Our results established investigational tool compound potential therapeutic agent COVID-19.