{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T20:37:23Z","timestamp":1789504643353,"version":"build-2803163510"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T00:00:00Z","timestamp":1602720000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T00:00:00Z","timestamp":1602720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>While the COVID-19 pandemic has spurred intense research and collaborative discovery worldwide, the development of a safe, effective, and targeted antiviral\u00a0from the ground up is time intensive.\u00a0Therefore, most antiviral discovery efforts are focused on the\u00a0re-purposing of clinical stage or approved drugs. While emerging data on drugs undergoing COVID-19 repurpose are intriguing,\u00a0there is an undeniable need to develop broad-spectrum antivirals to prevent future viral pandemics of unknown origin. The ideal drug to curtail rapid viral spread would be\u00a0a broad-acting agent with activity against a wide range of viruses. Such a drug would work by modulating host-proteins that are often shared by multiple virus families thereby enabling preemptive drug development and\u00a0therefore\u00a0rapid deployment at the onset of an outbreak. Targeting host-pathways and cellular\u00a0proteins that are hijacked by\u00a0viruses can potentially\u00a0offer broad-spectrum targets for the development of\u00a0future antiviral drugs. Such host-directed antivirals are also likely to offer a higher barrier to the\u00a0development\u00a0and selection of\u00a0drug\u00a0resistant mutations. Given that most\u00a0approved antivirals do not target host-proteins, we reinforce the need for the development of such antivirals that can be used in pre- and post-exposure populations.<\/jats:p>","DOI":"10.1186\/s12967-020-02476-9","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T14:03:38Z","timestamp":1602770618000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":100,"title":["A painful lesson from the COVID-19 pandemic: the need for broad-spectrum, host-directed antivirals"],"prefix":"10.1186","volume":"18","author":[{"given":"Vipul C.","family":"Chitalia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9617-9460","authenticated-orcid":false,"given":"Ali H.","family":"Munawar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,15]]},"reference":[{"key":"2476_CR1","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","volume":"579","author":"F Wu","year":"2020","unstructured":"Wu F, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579:265\u20139. https:\/\/doi.org\/10.1038\/s41586-020-2008-3.","journal-title":"Nature"},{"key":"2476_CR2","unstructured":"Novel Coronavirus (2019-nCoV) situation reports."},{"key":"2476_CR3","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.jhealeco.2016.01.012","volume":"47","author":"JA DiMasi","year":"2016","unstructured":"DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:20\u201333. https:\/\/doi.org\/10.1016\/j.jhealeco.2016.01.012.","journal-title":"J Health Econ"},{"key":"2476_CR4","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41421-020-0156-0","volume":"6","author":"J Liu","year":"2020","unstructured":"Liu J, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. https:\/\/doi.org\/10.1038\/s41421-020-0156-0.","journal-title":"Cell Discov"},{"key":"2476_CR5","doi-asserted-by":"publisher","first-page":"72","DOI":"10.5582\/bst.2020.01047","volume":"14","author":"J Gao","year":"2020","unstructured":"Gao J, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14:72\u20133.","journal-title":"Biosci Trends"},{"key":"2476_CR6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2012410","author":"J Geleris","year":"2020","unstructured":"Geleris J, et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020. https:\/\/doi.org\/10.1056\/NEJMoa2012410.","journal-title":"N Engl J Med"},{"key":"2476_CR7","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.8630","author":"ES Rosenberg","year":"2020","unstructured":"Rosenberg ES, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA. 2020. https:\/\/doi.org\/10.1001\/jama.2020.8630.","journal-title":"JAMA"},{"key":"2476_CR8","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2020.1834","author":"NJ Mercuro","year":"2019","unstructured":"Mercuro NJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2019. https:\/\/doi.org\/10.1001\/jamacardio.2020.1834.","journal-title":"JAMA Cardiol"},{"key":"2476_CR9","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.120.008662","author":"M Saleh","year":"2020","unstructured":"Saleh M, et al. The effect of chloroquine, hydroxychloroquine and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection. Circ Arrhythm Electrophysiol. 2020. https:\/\/doi.org\/10.1161\/CIRCEP.120.008662.","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"2476_CR10","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2020.05.014","author":"E Chorin","year":"2020","unstructured":"Chorin E, et al. QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine\/Azithromycin. Heart Rhythm. 2020. https:\/\/doi.org\/10.1016\/j.hrthm.2020.05.014.","journal-title":"Heart Rhythm"},{"key":"2476_CR11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2007764","author":"JH Beigel","year":"2020","unstructured":"Beigel JH, et al. Remdesivir for the Treatment of Covid-19\u2014preliminary report. N Engl J Med. 2020. https:\/\/doi.org\/10.1056\/NEJMoa2007764.","journal-title":"N Engl J Med"},{"key":"2476_CR12","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","volume":"181","author":"M Hoffmann","year":"2020","unstructured":"Hoffmann M, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271\u201380. https:\/\/doi.org\/10.1016\/j.cell.2020.02.052.","journal-title":"Cell"},{"key":"2476_CR13","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1128\/MCB.26.3.965-975.2006","volume":"26","author":"TS Kim","year":"2006","unstructured":"Kim TS, Heinlein C, Hackman RC, Nelson PS. Phenotypic analysis of mice lacking the Tmprss2-encoded protease. Mol Cell Biol. 2006;26:965\u201375. https:\/\/doi.org\/10.1128\/MCB.26.3.965-975.2006.","journal-title":"Mol Cell Biol"},{"key":"2476_CR14","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.coviro.2017.03.018","volume":"24","author":"M Laporte","year":"2017","unstructured":"Laporte M, Naesens L. Airway proteases: an emerging drug target for influenza and other respiratory virus infections. Curr Opin Virol. 2017;24:16\u201324. https:\/\/doi.org\/10.1016\/j.coviro.2017.03.018.","journal-title":"Curr Opin Virol"},{"key":"2476_CR15","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01815-18","author":"N Iwata-Yoshikawa","year":"2019","unstructured":"Iwata-Yoshikawa N, et al. TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J Virol. 2019. https:\/\/doi.org\/10.1128\/jvi.01815-18.","journal-title":"J Virol"},{"key":"2476_CR16","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.antiviral.2015.01.011","volume":"116","author":"Y Zhou","year":"2015","unstructured":"Zhou Y, et al. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. 2015;116:76\u201384. https:\/\/doi.org\/10.1016\/j.antiviral.2015.01.011.","journal-title":"Antiviral Res"},{"key":"2476_CR17","doi-asserted-by":"publisher","first-page":"e1073","DOI":"10.1002\/cti2.1073","volume":"8","author":"E Braun","year":"2019","unstructured":"Braun E, Sauter D. Furin-mediated protein processing in infectious diseases and cancer. Clin Transl Immunology. 2019;8:e1073. https:\/\/doi.org\/10.1002\/cti2.1073.","journal-title":"Clin Transl Immunology"},{"key":"2476_CR18","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1128\/aac.44.4.859-866.2000","volume":"44","author":"W Markland","year":"2000","unstructured":"Markland W, McQuaid TJ, Jain J, Kwong AD. Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon. Antimicrob Agents Chemother. 2000;44:859\u201366. https:\/\/doi.org\/10.1128\/aac.44.4.859-866.2000.","journal-title":"Antimicrob Agents Chemother"},{"key":"2476_CR19","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1038\/82191","volume":"6","author":"S Crotty","year":"2000","unstructured":"Crotty S, et al. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med. 2000;6:1375\u20139. https:\/\/doi.org\/10.1038\/82191.","journal-title":"Nat Med"},{"key":"2476_CR20","doi-asserted-by":"publisher","first-page":"104786","DOI":"10.1016\/j.antiviral.2020.104786","volume":"178","author":"KT Choy","year":"2020","unstructured":"Choy KT, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020;178:104786. https:\/\/doi.org\/10.1016\/j.antiviral.2020.104786.","journal-title":"Antiviral Res"},{"key":"2476_CR21","doi-asserted-by":"publisher","first-page":"E162","DOI":"10.1073\/pnas.1718806115","volume":"115","author":"F Ferron","year":"2018","unstructured":"Ferron F, et al. Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA. Proc Natl Acad Sci U S A. 2018;115:E162\u201371. https:\/\/doi.org\/10.1073\/pnas.1718806115.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"16","key":"2476_CR22","doi-asserted-by":"publisher","first-page":"8318","DOI":"10.1128\/JVI.01029-15","volume":"89","author":"AH de Wilde","year":"2015","unstructured":"de Wilde AH, Wannee KF, Scholte FEM, Goeman JJ, ten Dijke P, Snijder EJ, Kikkert M, van Martijn J, Hemert SP. A kinome-wide small interfering rna screen identifies proviral and antiviral host factors in severe acute respiratory syndrome coronavirus replication, including double-stranded rna-activated protein kinase and early secretory pathway proteins. J Virol. 2015;89(16):8318\u201333.","journal-title":"J Virol."},{"key":"2476_CR23","doi-asserted-by":"publisher","first-page":"e1007601","DOI":"10.1371\/journal.ppat.1007601","volume":"15","author":"M Lesch","year":"2019","unstructured":"Lesch M, et al. RNAi-based small molecule repositioning reveals clinically approved urea-based kinase inhibitors as broadly active antivirals. PLoS Pathog. 2019;15:e1007601. https:\/\/doi.org\/10.1371\/journal.ppat.1007601.","journal-title":"PLoS Pathog"},{"key":"2476_CR24","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.jphs.2014.07.001","volume":"127","author":"T Hayashi","year":"2015","unstructured":"Hayashi T. Sigma-1 receptor: the novel intracellular target of neuropsychotherapeutic drugs. J Pharmacol Sci. 2015;127:2\u20135. https:\/\/doi.org\/10.1016\/j.jphs.2014.07.001.","journal-title":"J Pharmacol Sci"},{"key":"2476_CR25","doi-asserted-by":"publisher","first-page":"6377","DOI":"10.1128\/JVI.03557-12","volume":"87","author":"M Friesland","year":"2013","unstructured":"Friesland M, Mingorance L, Chung J, Chisari FV, Gastaminza P. Sigma-1 receptor regulates early steps of viral RNA replication at the onset of hepatitis C virus infection. J Virol. 2013;87:6377\u201390. https:\/\/doi.org\/10.1128\/JVI.03557-12.","journal-title":"J Virol"},{"key":"2476_CR26","doi-asserted-by":"publisher","first-page":"eaav7999","DOI":"10.1126\/sciadv.aav7999","volume":"5","author":"S Yang","year":"2019","unstructured":"Yang S, et al. Control of antiviral innate immune response by protein geranylgeranylation. Sci Adv. 2019;5:eaav7999. https:\/\/doi.org\/10.1126\/sciadv.aav7999.","journal-title":"Sci Adv"},{"key":"2476_CR27","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1186\/s13148-019-0654-9","volume":"11","author":"Z Nehme","year":"2019","unstructured":"Nehme Z, Pasquereau S, Herbein G. Control of viral infections by epigenetic-targeted therapy. Clin Epigenetics. 2019;11:55. https:\/\/doi.org\/10.1186\/s13148-019-0654-9.","journal-title":"Clin Epigenetics"},{"key":"2476_CR28","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.antiviral.2018.05.005","volume":"155","author":"S Chaudhuri","year":"2018","unstructured":"Chaudhuri S, Symons JA, Deval J. Innovation and trends in the development and approval of antiviral medicines: 1987\u20132017 and beyond. Antiviral Res. 2018;155:76\u201388. https:\/\/doi.org\/10.1016\/j.antiviral.2018.05.005.","journal-title":"Antiviral Res"},{"key":"2476_CR29","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1128\/CMR.00102-15","volume":"29","author":"E De Clercq","year":"2016","unstructured":"De Clercq E, Li G. Approved antiviral drugs over the past 50 years. Clin Microbiol Rev. 2016;29:695\u2013747. https:\/\/doi.org\/10.1128\/CMR.00102-15.","journal-title":"Clin Microbiol Rev"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-020-02476-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-020-02476-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-020-02476-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,15]],"date-time":"2021-10-15T15:26:05Z","timestamp":1634311565000},"score":1,"resource":{"primary":{"URL":"https:\/\/translational-medicine.biomedcentral.com\/articles\/10.1186\/s12967-020-02476-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,15]]},"references-count":29,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["2476"],"URL":"https:\/\/doi.org\/10.1186\/s12967-020-02476-9","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,15]]},"assertion":[{"value":"18 April 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 October 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no commercial or competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"390"}}