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Upon entry into infected cells, the nucleocapsid (N) protein of coronavirus becomes heavily phosphorylated within its central Ser\u2010Arg domain by host kinase GSK\u20103, which triggers genomic RNA unpackaging and facilitates its recruitment to the replication transcription complex. Although initially considered a promising antiviral strategy, inhibiting N hyperphosphorylation requires high concentrations of kinase inhibitor and is impractical to achieve by conventional pharmacological means.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental approach<\/jats:title>\n                    <jats:p>We investigated the effect of GSK\u20103 inhibition on SARS\u2010CoV\u20102 replication in Calu\u20103 and Vero E6 cells. The dose\u2010dependent effect of the GSK\u20103 inhibitor to block N hyperphosphorylation was examined in 293T cells heterologously expressing the viral protein. Liquid chromatography\u2013tandem mass spectrometry analysis was performed to evaluate the phosphorylation profile of the purified N protein.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key results<\/jats:title>\n                    <jats:p>\n                      GSK\u20103 inhibition delays the release of progeny virus from infected cells. N hyperphosphorylation relies on a complex, redundant priming mechanism and exhibits strong cooperativity, which together contribute to resistance against GSK\u20103 inhibitors. The N\n                      <jats:sup>R203M<\/jats:sup>\n                      and N\n                      <jats:sup>R203K\/G204R<\/jats:sup>\n                      mutations\u2014present in the delta and omicron variants of concern (VOCs), respectively\u2014reduce the efficiency of GSK\u20103\u2010mediated phosphorylation. We discovered a novel pharmacological tool combining niclosamide and alectinib that partially degrades GSK\u20103 and restores the sensitivity of N hyperphosphorylation to the clinically tested GSK\u20103 inhibitor, enzastaurin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and implications<\/jats:title>\n                    <jats:p>This work provides the biochemical basis for a novel approach to treat COVID\u201019 by synergistically repositioning two FDA\u2010approved drugs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70679","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T06:52:04Z","timestamp":1790319124000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Repositioning niclosamide and alectinib to inhibit the hyperphosphorylation of SARS\u2010CoV\u20102's nucleocapsid protein"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6374-3149","authenticated-orcid":false,"given":"Song","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmacology Yale School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4747-2681","authenticated-orcid":false,"given":"Zunyu","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yale School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4814-7573","authenticated-orcid":false,"given":"Jean","family":"Kanyo","sequence":"additional","affiliation":[{"name":"Keck MS &amp; 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