{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:24:10Z","timestamp":1785803050535,"version":"3.56.0"},"reference-count":33,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Mathers Foundation","award":["W81XWH2110029"],"award-info":[{"award-number":["W81XWH2110029"]}]},{"name":"Mathers Foundation","award":["T32AI095213"],"award-info":[{"award-number":["T32AI095213"]}]},{"name":"Massachusetts Consortium on Pathogen Readiness","award":["W81XWH2110029"],"award-info":[{"award-number":["W81XWH2110029"]}]},{"name":"Massachusetts Consortium on Pathogen Readiness","award":["T32AI095213"],"award-info":[{"award-number":["T32AI095213"]}]},{"DOI":"10.13039\/100000005","name":"Department of Defense COVID-19 Expansion for AIRe Program","doi-asserted-by":"publisher","award":["W81XWH2110029"],"award-info":[{"award-number":["W81XWH2110029"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Department of Defense COVID-19 Expansion for AIRe Program","doi-asserted-by":"publisher","award":["T32AI095213"],"award-info":[{"award-number":["T32AI095213"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["W81XWH2110029"],"award-info":[{"award-number":["W81XWH2110029"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["T32AI095213"],"award-info":[{"award-number":["T32AI095213"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["COVID"],"abstract":"<jats:p>Coronavirus disease 2019 (COVID-19) has had devastating effects worldwide, with particularly high morbidity and mortality in outbreaks on residential care facilities. Amantadine, originally licensed as an antiviral agent for therapy and prophylaxis against influenza A virus, has beneficial effects on patients with Parkinson\u2019s disease and is used for treatment of Parkinson\u2019s disease, multiple sclerosis, acquired brain injury, and various other neurological disorders. Recent observational data suggest an inverse relationship between the use of amantadine and COVID-19. Adamantanes, including amantadine and rimantadine, are reported to have in vitro activity against severe acute respiratory syndrome coronavirus (SARS-CoV) and, more recently, SARS-CoV-2. We hypothesized that adamantanes have antiviral activity against SARS-CoV-2, including variant strains. To assess the activity of adamantanes against SARS-CoV-2, we used in vitro and in vivo models of infection. We established that amantadine, rimantadine, and tromantadine inhibit the growth of SARS-CoV-2 in vitro in cultured human epithelial cells. While neither rimantadine nor amantadine reduces lung viral titers in mice infected with mouse-adapted SARS-CoV-2, rimantadine significantly reduces viral titers in the lungs in golden Syrian hamsters infected with SARS-CoV-2. In summary, rimantadine has antiviral activity against SARS-CoV-2 in human alveolar epithelial cells and in the hamster model of SARS-CoV-2 lung infection. The evaluation of amantadine or rimantadine in human randomized controlled trials can definitively address applications for the treatment or prevention of COVID-19.<\/jats:p>","DOI":"10.3390\/covid2110111","type":"journal-article","created":{"date-parts":[[2022,10,29]],"date-time":"2022-10-29T23:45:00Z","timestamp":1667087100000},"page":"1551-1563","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Anti-SARS-CoV-2 Activity of Adamantanes In Vitro and in Animal Models of Infection"],"prefix":"10.3390","volume":"2","author":[{"given":"Sun-Young","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0603-9961","authenticated-orcid":false,"given":"Zhiru","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1309-570X","authenticated-orcid":false,"given":"Ping","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0369-9067","authenticated-orcid":false,"given":"Lindsay G. A.","family":"McKay","sequence":"additional","affiliation":[{"name":"Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2596-0468","authenticated-orcid":false,"given":"Nadia","family":"Storm","sequence":"additional","affiliation":[{"name":"Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5435-8364","authenticated-orcid":false,"given":"Anthony","family":"Griffiths","sequence":"additional","affiliation":[{"name":"Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming Da","family":"Qu","sequence":"additional","affiliation":[{"name":"Division of Infectious Disease & Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Finberg","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7471-4530","authenticated-orcid":false,"given":"Mohan","family":"Somasundaran","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2556-9100","authenticated-orcid":false,"given":"Jennifer P.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1093\/cid\/ciy874","article-title":"Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza A","volume":"68","author":"Uyeki","year":"2019","journal-title":"Clin. Infect Dis."},{"key":"ref_2","first-page":"110","article-title":"Use of amantadine in a patient with SARS-CoV-2","volume":"93","author":"Araujo","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_3","first-page":"284","article-title":"Does amantadine have a protective effect against COVID-19?","volume":"54","year":"2020","journal-title":"Pol. J. Neurol. Neurosurg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"102163","DOI":"10.1016\/j.msard.2020.102163","article-title":"Adamantanes might be protective from COVID-19 in patients with neurological diseases: Multiple sclerosis, parkinsonism and cognitive impairment","volume":"42","author":"Rejdak","year":"2020","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"704186","DOI":"10.3389\/fneur.2021.704186","article-title":"Effect of Pre-exposure Use of Amantadine on COVID-19 Infection: A Hospital-Based Cohort Study in Patients with Parkinson\u2019s Disease or Multiple Sclerosis","volume":"12","author":"Kamel","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1128\/AAC.4.4.421","article-title":"In vitro antiviral activity and preliminary clinical trials of a new adamantane compound","volume":"4","author":"Mathur","year":"1973","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1128\/JVI.02972-13","article-title":"Novel treatment with neuroprotective and antiviral properties against a neuroinvasive human respiratory virus","volume":"88","author":"Brison","year":"2014","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jcv.2004.03.003","article-title":"In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds","volume":"31","author":"Chen","year":"2004","journal-title":"J. Clin. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.chembiol.2005.01.006","article-title":"The adamantane-derived bananins are potent inhibitors of the helicase activities and replication of SARS coronavirus","volume":"12","author":"Tanner","year":"2005","journal-title":"Chem. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.cell.2020.10.030","article-title":"Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells","volume":"184","author":"Daniloski","year":"2021","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1038\/s41596-021-00491-8","article-title":"Engineering SARS-CoV-2 using a reverse genetic system","volume":"16","author":"Xie","year":"2021","journal-title":"Nat. Protoc."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"ter Meulen, J., van den Brink, E.N., Poon, L.L., Marissen, W.E., Leung, C.S., Cox, F., Cheung, C.Y., Bakker, A.Q., Bogaards, J.A., and van Deventer, E. (2006). Human monoclonal antibody combination against SARS coronavirus: Synergy and coverage of escape mutants. PLoS Med., 3.","DOI":"10.1371\/journal.pmed.0030237"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"106755","DOI":"10.1016\/j.cct.2022.106755","article-title":"The use of amantadine in the prevention of progression and treatment of COVID-19 symptoms in patients infected with the SARS-CoV-2 virus (COV-PREVENT): Study rationale and design","volume":"116","author":"Rejdak","year":"2022","journal-title":"Contemp. Clin. Trials"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fink, K., Nitsche, A., Neumann, M., Grossegesse, M., Eisele, K.H., and Danysz, W. (2021). Amantadine Inhibits SARS-CoV-2 In Vitro. Viruses, 13.","DOI":"10.3390\/v13040539"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Gammeltoft, K.A., Galli, A., Offersgaard, A., Fahnoe, U., Ramirez, S., Bukh, J., and Gottwein, J.M. (2021). Efficacy of Ion-Channel Inhibitors Amantadine, Memantine and Rimantadine for the Treatment of SARS-CoV-2 In Vitro. Viruses, 13.","DOI":"10.3390\/v13102082"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.cell.2020.09.050","article-title":"A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice","volume":"183","author":"Leist","year":"2020","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/0041-008X(69)90066-0","article-title":"The toxicologic and pharmacologic properties of amantadine hydrochloride","volume":"15","author":"Vernier","year":"1969","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2428","DOI":"10.1093\/cid\/ciaa644","article-title":"Simulation of the Clinical and Pathological Manifestations of Coronavirus Disease 2019 (COVID-19) in a Golden Syrian Hamster Model: Implications for Disease Pathogenesis and Transmissibility","volume":"71","author":"Chan","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1080\/22221751.2020.1858177","article-title":"Defining the Syrian hamster as a highly susceptible preclinical model for SARS-CoV-2 infection","volume":"9","author":"Rosenke","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16587","DOI":"10.1073\/pnas.2009799117","article-title":"Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development","volume":"117","author":"Imai","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/s41586-020-2342-5","article-title":"Pathogenesis and transmission of SARS-CoV-2 in golden hamsters","volume":"583","author":"Sia","year":"2020","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1124\/jpet.118.247650","article-title":"Pharmacokinetic\/Pharmacodynamic Correlation Analysis of Amantadine for Levodopa-Induced Dyskinesia","volume":"367","author":"Brigham","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1128\/AAC.32.11.1699","article-title":"Pharmacokinetics and metabolism of rimantadine hydrochloride in mice and dogs","volume":"32","author":"Hoffman","year":"1988","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1038\/s42003-021-02940-2","article-title":"Author Correction: Amantadine inhibits known and novel ion channels encoded by SARS-CoV-2 in vitro","volume":"4","author":"Jeppesen","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1038\/s41594-020-00536-8","article-title":"Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers","volume":"27","author":"Mandala","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1038\/s42003-022-03669-2","article-title":"How many SARS-CoV-2 \u201cviroporins\u201d are really ion channels?","volume":"5","author":"Harrison","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s40120-019-0144-1","article-title":"Bioavailability and Pharmacokinetics of Once-Daily Amantadine Extended-Release Tablets in Healthy Volunteers: Results from Three Randomized, Crossover, Open-Label, Phase 1 Studies","volume":"8","author":"deVries","year":"2019","journal-title":"Neurol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1128\/AAC.23.3.458","article-title":"Differences in side effects of amantadine hydrochloride and rimantadine hydrochloride relate to differences in pharmacokinetics","volume":"23","author":"Hayden","year":"1983","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/S0272-2712(18)30721-2","article-title":"Antiviral Chemotherapyand Prophylaxis of Viral Respiratory Disease","volume":"7","author":"Sperber","year":"1987","journal-title":"Clin. Lab. Med."},{"key":"ref_30","unstructured":"(2022, October 03). U.S. National Library of Medicine, Available online: https:\/\/clinicaltrials.gov\/."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1001\/archinte.160.10.1485","article-title":"Comparison of central nervous system adverse effects of amantadine and rimantadine used as sequential prophylaxis of influenza A in elderly nursing home patients","volume":"160","author":"Keyser","year":"2000","journal-title":"Arch. Intern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1177\/135965350701200302","article-title":"Amantadine-oseltamivir combination therapy for H5N1 influenza virus infection in mice","volume":"12","author":"Ilyushina","year":"2007","journal-title":"Antivir. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1128\/AAC.01012-08","article-title":"Effects of double combinations of amantadine, oseltamivir, and ribavirin on influenza A (H5N1) virus infections in cell culture and in mice","volume":"53","author":"Smee","year":"2009","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["COVID"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2673-8112\/2\/11\/111\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:04:54Z","timestamp":1760144694000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2673-8112\/2\/11\/111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,28]]},"references-count":33,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["covid2110111"],"URL":"https:\/\/doi.org\/10.3390\/covid2110111","relation":{},"ISSN":["2673-8112"],"issn-type":[{"value":"2673-8112","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,28]]}}}