{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:52:31Z","timestamp":1785214351484,"version":"3.55.0"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Viruses exploit host kinases to phosphorylate their proteins, enabling viral replication and interference with host-cell functions. Understanding phosphorylation in SARS-CoV-2 proteins necessitates identifying viral phosphoproteins, their phosphosites, and the host kinase\u2013viral protein interactions critical for evading host antiviral responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Employing the protein kinase substrate sequence-preference motifs derived by Poll B G. <jats:italic>et. al<\/jats:italic>., 2024, we performed kinase-substrate phosphomotif pattern analysis on the SARS-CoV-2 proteome. We identified major host kinases by analyzing SARS-CoV-2 perturbed phosphoproteomes from various studies and cell systems. These kinases were subjected to interactome analysis and literature-based validation for the impact of kinase inhibitors on infection. Further, conservation of viral phosphosites across SARS CoV-2 variants were also assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The human kinome\u2013substrate phosphomotif analysis predicted 49 kinases capable of phosphorylating 639 phosphosites across 33 SARS-CoV-2 proteins. From these, 24 kinases were also perturbed in SARS-CoV-2-infected phosphoproteomes. Literature review identified seven kinases, including MAP2K1, whose inhibition may reduce viral replication. MAP2K1 was found to target key viral phosphosites, including N protein (S206, T198) and ORF9b (S50), conserved across SARS-CoV-2 variants. Docking analysis showed MAP2K1 forms stronger, closer interactions with N protein compared to SRPK1, highlighting MAP2K1 as a potential host kinase for therapeutic targeting in SARS-CoV-2 infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion and Conclusions<\/jats:title><jats:p>This study presents a framework for predicting human kinases of specific SARS-CoV-2 protein phosphosites by integrating kinase specificity, virus\u2013host interactions, and post-translational modifications. MAP2K1 was identified as a key host kinase, showing stronger interactions than SRPK1, and is proposed as an antiviral drug target for repurposing in SARS-CoV-2 infections.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1554760","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T05:47:22Z","timestamp":1752126442000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Analysis of phosphomotifs coupled to phosphoproteome and interactome unveils potential human kinase substrate proteins in SARS-CoV-2"],"prefix":"10.3389","volume":"15","author":[{"given":"Vineetha","family":"Shaji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Rafi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukhtar","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athira Perunelly","family":"Gopalakrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sowmya","family":"Soman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amjesh","family":"Revikumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesh","family":"Prasad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhithaj","family":"Jayanandan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh","family":"Raju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1016\/j.sjbs.2020.12.053","article-title":"Genome composition and genetic characterization of SARS-CoV-2","volume":"28","author":"Al-Qaaneh","year":"2021","journal-title":"Saudi J. 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