{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:44:25Z","timestamp":1792802665148,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011358","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000}}],"reference-count":83,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T00:00:00Z","timestamp":1682899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Board of Research in Nuclear Sciences, Department of Atomic Energy, India","award":["54\/14\/13\/2020-BRNS"],"award-info":[{"award-number":["54\/14\/13\/2020-BRNS"]}],"id":[{"id":"https:\/\/ror.org\/02m388s04","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Science & Engineering Research Board, Department of Science and Technology, India","award":["EMR\/2017\/002022"],"award-info":[{"award-number":["EMR\/2017\/002022"]}]},{"name":"Science & Engineering Research Board, Department of Science and Technology, India","award":["IPA\/2020\/000091"],"award-info":[{"award-number":["IPA\/2020\/000091"]}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["INV-005948"],"award-info":[{"award-number":["INV-005948"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) poses enormous challenge in the development of broad-spectrum antivirals that are effective against the existing and emerging viral strains. Virus entry through endocytosis represents an attractive target for drug development, as inhibition of this early infection step should block downstream infection processes, and potentially inhibit viruses sharing the same entry route. In this study, we report the identification of 1,3-diphenylurea (DPU) derivatives (DPUDs) as a new class of endocytosis inhibitors, which broadly restricted entry and replication of several SARS-CoV-2 and IAV strains. Importantly, the DPUDs did not induce any significant cytotoxicity at concentrations effective against the viral infections. Examining the uptake of cargoes specific to different endocytic pathways, we found that DPUDs majorly affected clathrin-mediated endocytosis, which both SARS-CoV-2 and IAV utilize for cellular entry. In the DPUD-treated cells, although virus binding on the cell surface was unaffected, internalization of both the viruses was drastically reduced. Since compounds similar to the DPUDs were previously reported to transport anions including chloride (Cl\n                    <jats:sup>-<\/jats:sup>\n                    ) across lipid membrane and since intracellular Cl\n                    <jats:sup>-<\/jats:sup>\n                    concentration plays a critical role in regulating vesicular trafficking, we hypothesized that the observed defect in endocytosis by the DPUDs could be due to altered Cl\n                    <jats:sup>-<\/jats:sup>\n                    gradient across the cell membrane. Using\n                    <jats:italic>in vitro<\/jats:italic>\n                    assays we demonstrated that the DPUDs transported Cl\n                    <jats:sup>-<\/jats:sup>\n                    into the cell and led to intracellular Cl\n                    <jats:sup>-<\/jats:sup>\n                    accumulation, which possibly affected the endocytic machinery by perturbing intracellular Cl\n                    <jats:sup>-<\/jats:sup>\n                    homeostasis. Finally, we tested the DPUDs in mice challenged with IAV and mouse-adapted SARS-CoV-2 (MA 10). Treatment of the infected mice with the DPUDs led to remarkable body weight recovery, improved survival and significantly reduced lung viral load, highlighting their potential for development as broad-spectrum antivirals.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011358","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T13:30:00Z","timestamp":1682947800000},"page":"e1011358","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Identification of diphenylurea derivatives as novel endocytosis inhibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo"],"prefix":"10.1371","volume":"19","author":[{"given":"Nirmal","family":"Kumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irshad Maajid","family":"Taily","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charandeep","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahil","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raju S.","family":"Rajmani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debajyoti","family":"Chakraborty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshul","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishan Gopal","family":"Thakur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghavan","family":"Varadarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh P.","family":"Ringe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabal","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0808-2392","authenticated-orcid":true,"given":"Indranil","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,5,1]]},"reference":[{"key":"ppat.1011358.ref001","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1099\/vir.0.059477-0","article-title":"Entry of influenza A virus: host factors and antiviral targets","volume":"95","author":"TO Edinger","year":"2014","journal-title":"Journal of General Virology"},{"key":"ppat.1011358.ref002","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.12688\/f1000research.19694.1","article-title":"Targeting viral entry as a strategy for broad-spectrum antivirals","volume":"8","author":"M Mazzon","year":"2019","journal-title":"F1000Res"},{"key":"ppat.1011358.ref003","first-page":"14","article-title":"Mutations in the SARS-CoV-2 RNA-dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms","author":"LJ Stevens","year":"2022","journal-title":"Sci Transl Med"},{"key":"ppat.1011358.ref004","article-title":"De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report.","author":"S Gandhi","year":"2021","journal-title":"medRxiv. 2021"},{"key":"ppat.1011358.ref005","article-title":"Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir","author":"Y Hu","year":"2022","journal-title":"Pharmacology and Toxicology"},{"key":"ppat.1011358.ref006","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1007\/s10096-020-03840-9","article-title":"Influenza and antiviral resistance: an overview","volume":"39","author":"T. 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