tetano
Editor, Senior Moderator
Nat Commun
. 2026 May 6.
doi: 10.1038/s41467-026-72615-1. Online ahead of print.
MELK inhibition disrupts actin cytoskeleton and broadly restricts human coronavirus infections
Kuai Yu[SUP] #[/SUP][SUP] 1 [/SUP], Qiaorui Yao[SUP] #[/SUP][SUP] 1 2 [/SUP], Dong Wang[SUP] #[/SUP][SUP] 1 3 [/SUP], Qingtao Hu[SUP] #[/SUP][SUP] 1 3 [/SUP], Dandan Li[SUP] #[/SUP][SUP] 1 [/SUP], Fang Li[SUP] 1 [/SUP], Fenghua Chen[SUP] 1 [/SUP], Jingyi Su[SUP] 1 [/SUP], Ting Huang[SUP] 1 [/SUP], Qing Zhang[SUP] 4 [/SUP], Zishuo Lin[SUP] 5 [/SUP], Wei Ran[SUP] 1 [/SUP], Yiliang Wang[SUP] 1 [/SUP], Yuzheng Zhou[SUP] 6 [/SUP], Shuai Wen[SUP] 1 [/SUP], Yuting Lin[SUP] 1 [/SUP], Yaming Jiu[SUP] 7 8 [/SUP], Jingxian Zhao[SUP] 9 10 [/SUP], Jincun Zhao[SUP] 11 12 13 14 [/SUP]
Affiliations
Protein kinases regulate numerous critical biological processes in eukaryotic cells and are important targets for drug development. However, the common functional protein kinases and corresponding inhibitors with broad-spectrum therapeutic potential for human coronavirus infections remain largely unknown. By integrating global phosphoproteomics and high-content screening, we identify maternal embryonic leucine zipper kinase (MELK) as a common kinase required for the infections of multiple human coronaviruses currently circulating in the population. Inhibition of MELK activity by OTSSP167, or genetic depletion of its expression, exhibits broad antiviral effects in cells, human airway organoids as well as in mice under a prophylactic setting. Intriguingly, super-resolution imaging reveals that MELK colocalizes with the cellular actin cytoskeleton that is required for viral infection. Subsequently, live-cell imaging demonstrates that OTSSP167 treatment disrupts the dynamics of actin cytoskeleton. Mechanistic analysis reveals that MELK directly phosphorylates a key actin-depolymerizing protein, cofilin-1 at S3 and T70, thereby suppressing its actin-severing activity. Inhibiting MELK activity or expression activates cofilin-1 and disrupts actin filament formation, thereby impeding multiple steps of viral life cycle. Collectively, our study reveals a common regulation of coronavirus infections by MELK through modulation of actin cytoskeleton, and the broad antiviral effect of OTSSP167 as a novel actin cytoskeleton modulator.
. 2026 May 6.
doi: 10.1038/s41467-026-72615-1. Online ahead of print.
MELK inhibition disrupts actin cytoskeleton and broadly restricts human coronavirus infections
Kuai Yu[SUP] #[/SUP][SUP] 1 [/SUP], Qiaorui Yao[SUP] #[/SUP][SUP] 1 2 [/SUP], Dong Wang[SUP] #[/SUP][SUP] 1 3 [/SUP], Qingtao Hu[SUP] #[/SUP][SUP] 1 3 [/SUP], Dandan Li[SUP] #[/SUP][SUP] 1 [/SUP], Fang Li[SUP] 1 [/SUP], Fenghua Chen[SUP] 1 [/SUP], Jingyi Su[SUP] 1 [/SUP], Ting Huang[SUP] 1 [/SUP], Qing Zhang[SUP] 4 [/SUP], Zishuo Lin[SUP] 5 [/SUP], Wei Ran[SUP] 1 [/SUP], Yiliang Wang[SUP] 1 [/SUP], Yuzheng Zhou[SUP] 6 [/SUP], Shuai Wen[SUP] 1 [/SUP], Yuting Lin[SUP] 1 [/SUP], Yaming Jiu[SUP] 7 8 [/SUP], Jingxian Zhao[SUP] 9 10 [/SUP], Jincun Zhao[SUP] 11 12 13 14 [/SUP]
Affiliations
- PMID: 42091603
- DOI: 10.1038/s41467-026-72615-1
Protein kinases regulate numerous critical biological processes in eukaryotic cells and are important targets for drug development. However, the common functional protein kinases and corresponding inhibitors with broad-spectrum therapeutic potential for human coronavirus infections remain largely unknown. By integrating global phosphoproteomics and high-content screening, we identify maternal embryonic leucine zipper kinase (MELK) as a common kinase required for the infections of multiple human coronaviruses currently circulating in the population. Inhibition of MELK activity by OTSSP167, or genetic depletion of its expression, exhibits broad antiviral effects in cells, human airway organoids as well as in mice under a prophylactic setting. Intriguingly, super-resolution imaging reveals that MELK colocalizes with the cellular actin cytoskeleton that is required for viral infection. Subsequently, live-cell imaging demonstrates that OTSSP167 treatment disrupts the dynamics of actin cytoskeleton. Mechanistic analysis reveals that MELK directly phosphorylates a key actin-depolymerizing protein, cofilin-1 at S3 and T70, thereby suppressing its actin-severing activity. Inhibiting MELK activity or expression activates cofilin-1 and disrupts actin filament formation, thereby impeding multiple steps of viral life cycle. Collectively, our study reveals a common regulation of coronavirus infections by MELK through modulation of actin cytoskeleton, and the broad antiviral effect of OTSSP167 as a novel actin cytoskeleton modulator.