Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 and a variant of concern in ferrets

Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 and a variant of concern in ferrets | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 and a variant of concern in ferrets Richard Plemper, Robert Cox, Josef Wolf, Carolin Lieber, Julien Sourimant, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-662905/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Nov, 2021 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Remdesivir is the only small-molecule antiviral approved to date for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterized the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibited SARS-CoV-2, including variants of concern (VoC) in cell culture. Oral GS-621763 was efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduced SARS-CoV-2 burden to near-undetectable levels. When dosed therapeutically against VoC P.1 gamma (γ), oral GS-621763 blocked virus replication and prevented transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection. Virology Oral Bioavailability Variants of Concern Relevant Animal Model Virus Replication Full Text Additional Declarations Yes there is potential Competing Interest. All authors affiliated with Gilead Sciences may hold stock or stock options in Gilead Sciences Inc. R.K.P. was the principal investigator of a Gilead-sponsored research agreement with Georgia State University. He has received funding from Gilead Sciences Inc. to support parts of this work. All other authors declare no competing interests. Supplementary Files SupplementaryInformation.pdf Supplementary Information Supplementarydataset1.html Supplementary dataset 1 Supplementarydataset2.html Supplementary dataset 2 Cite Share Download PDF Status: Published Journal Publication published 05 Nov, 2021 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-662905","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":42624502,"identity":"e1a7f496-6d78-4761-affd-792ea3333725","order_by":0,"name":"Richard Plemper","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYFAC5gYwxQ/lEaOFEaJFsoFkLQYHiNViPrux8dHNHTb5xueXP5NgqLBObCCkRebOwWbj3DNplttuvDGTYDiTTliLhERim3Ru22EDsxtn2CQY2w4TpaX9d27bfwPjGcefSTD+I05LG3Nu2wEDA/4GMwnGBmK0yBxsls49k2wgcYPH2CLhWLoxYS3SzQc/5+6wM+DvP/7wxocaa1mCWhgkGKBRI5HAwJBAUDmKFv4DRKkfBaNgFIyCEQgACEI/h121D5IAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-2034-2107","institution":"Georgia State University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Richard","middleName":"","lastName":"Plemper","suffix":""},{"id":42624503,"identity":"fb461759-2b63-4ccd-969d-f02f9c906655","order_by":1,"name":"Robert Cox","email":"","orcid":"https://orcid.org/0000-0003-0620-1674","institution":"Georgia State University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Cox","suffix":""},{"id":42624504,"identity":"8ffeba9b-b80f-44dd-ae8c-1827eaee953d","order_by":2,"name":"Josef Wolf","email":"","orcid":"","institution":"Georgia State University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Josef","middleName":"","lastName":"Wolf","suffix":""},{"id":42624505,"identity":"0ae5d103-1654-4f14-95d3-65369e81782a","order_by":3,"name":"Carolin Lieber","email":"","orcid":"","institution":"Georgia State University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Carolin","middleName":"","lastName":"Lieber","suffix":""},{"id":42624506,"identity":"a6ea2aa3-8d9a-490f-ad2f-816fe24f6eb5","order_by":4,"name":"Julien Sourimant","email":"","orcid":"https://orcid.org/0000-0002-1660-1666","institution":"Georgia State University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Julien","middleName":"","lastName":"Sourimant","suffix":""},{"id":42624507,"identity":"99fa0877-2fcc-49b7-b46d-1081420a772b","order_by":5,"name":"Michelle Lin","email":"","orcid":"https://orcid.org/0000-0002-6925-9948","institution":"University of Washington","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michelle","middleName":"","lastName":"Lin","suffix":""},{"id":42624508,"identity":"394282f7-9ef0-4660-b238-bcb9aa37b3b9","order_by":6,"name":"Darius Babusis","email":"","orcid":"https://orcid.org/0000-0001-5599-1671","institution":"Gilead Sciences (United States)","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Darius","middleName":"","lastName":"Babusis","suffix":""},{"id":42624509,"identity":"55d3b31a-5495-4ed6-ac06-0511f9d8b516","order_by":7,"name":"Venice Du Pont","email":"","orcid":"","institution":"Gilead Sciences Inc.","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Venice","middleName":"","lastName":"Du Pont","suffix":""},{"id":42624510,"identity":"8a18a85c-4faf-4383-af72-ab5af975e4a6","order_by":8,"name":"Julie Chan","email":"","orcid":"","institution":"Gilead Sciences Inc.","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Julie","middleName":"","lastName":"Chan","suffix":""},{"id":42624511,"identity":"976a5126-f224-4f17-ac5c-3b74370b3236","order_by":9,"name":"Kim Barrett","email":"","orcid":"","institution":"Gilead Sciences Inc.","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kim","middleName":"","lastName":"Barrett","suffix":""},{"id":42624512,"identity":"b685c46f-06b2-4e93-9149-130a8f37f005","order_by":10,"name":"Rao Kalla","email":"","orcid":"","institution":"Gilead Sciences Inc.","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rao","middleName":"","lastName":"Kalla","suffix":""},{"id":42624513,"identity":"3724e9f0-964c-4f2b-aaec-68a35fbd90eb","order_by":11,"name":"Kwon Chun","email":"","orcid":"","institution":"Gilead Sciences, Inc.","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kwon","middleName":"","lastName":"Chun","suffix":""},{"id":42624514,"identity":"8b23fcfb-d20c-4443-a786-0e157f8c6f96","order_by":12,"name":"Richard Mackman","email":"","orcid":"","institution":"Gilead Sciences, Inc.","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Richard","middleName":"","lastName":"Mackman","suffix":""},{"id":42624515,"identity":"86de921a-01fb-49c2-a10a-54381934878e","order_by":13,"name":"Chengjin Ye","email":"","orcid":"","institution":"Texas Biomedical Research Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chengjin","middleName":"","lastName":"Ye","suffix":""},{"id":42624516,"identity":"a246a579-a4b6-4c63-8ab4-c8d4f53509ce","order_by":14,"name":"Tomas Cihlar","email":"","orcid":"","institution":"Gilead Sciences, Inc.","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tomas","middleName":"","lastName":"Cihlar","suffix":""},{"id":42624517,"identity":"01cd8217-7112-4cfa-b71c-60dd4dd3d8d5","order_by":15,"name":"Luis Martinez-Sobrido","email":"","orcid":"https://orcid.org/0000-0001-7084-0804","institution":"Texas Biomedical Research Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Luis","middleName":"","lastName":"Martinez-Sobrido","suffix":""},{"id":42624518,"identity":"11b706fb-e41e-425a-a182-8694c160cfe7","order_by":16,"name":"Alexander Greninger","email":"","orcid":"","institution":"University of Washington","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Greninger","suffix":""},{"id":42624519,"identity":"c1607841-f067-4aea-a2b6-16c3f7dd960c","order_by":17,"name":"John Bilello","email":"","orcid":"https://orcid.org/0000-0003-4327-1727","institution":"Gilead","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"John","middleName":"","lastName":"Bilello","suffix":""}],"badges":[],"createdAt":"2021-06-26 23:20:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-662905/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-662905/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-021-26760-4","type":"published","date":"2021-11-05T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":15778340,"identity":"735414f6-e871-4156-859f-6c9cc74b3a23","added_by":"auto","created_at":"2021-11-22 15:28:10","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1134260,"visible":true,"origin":"","legend":"","description":"","filename":"Coxetal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-662905/v1_covered.pdf"},{"id":13663821,"identity":"eef9794a-0cc9-44bf-9e87-fd755c901686","added_by":"auto","created_at":"2021-09-17 10:38:42","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1129327,"visible":true,"origin":"","legend":"","description":"","filename":"Coxetal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-662905/v1_covered.pdf"},{"id":11952899,"identity":"5d16c8b7-9b7b-4856-985d-4b57411292cc","added_by":"auto","created_at":"2021-07-30 14:22:35","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1125731,"visible":true,"origin":"","legend":"","description":"","filename":"Coxetal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-662905/v1_covered.pdf"},{"id":11952896,"identity":"73328fd9-f766-4497-bc52-ba382e1474d0","added_by":"auto","created_at":"2021-07-30 14:22:28","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":138911,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"SupplementaryInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-662905/v1/32487fceb9e9c28fdbc73346.pdf"},{"id":11952897,"identity":"46d3a180-be9b-49ba-8da1-a17d8c4c85d9","added_by":"auto","created_at":"2021-07-30 14:22:28","extension":"html","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13580452,"visible":true,"origin":"","legend":"Supplementary dataset 1","description":"","filename":"Supplementarydataset1.html","url":"https://assets-eu.researchsquare.com/files/rs-662905/v1/2e9fab838be9d6124bd4fb32.html"},{"id":11952898,"identity":"85950eeb-1316-499d-ad70-a2958407dd43","added_by":"auto","created_at":"2021-07-30 14:22:28","extension":"html","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":9663004,"visible":true,"origin":"","legend":"Supplementary dataset 2","description":"","filename":"Supplementarydataset2.html","url":"https://assets-eu.researchsquare.com/files/rs-662905/v1/49f90bff234d802123b77d80.html"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nAll authors affiliated with Gilead Sciences may hold stock or stock options in Gilead Sciences Inc. R.K.P. was the principal investigator of a Gilead-sponsored research agreement with Georgia State University. He has received funding from Gilead Sciences Inc. to support parts of this work. All other authors declare no competing interests.","formattedTitle":"Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 and a variant of concern in ferrets","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-662905/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Oral Bioavailability, Variants of Concern, Relevant Animal Model, Virus Replication","lastPublishedDoi":"10.21203/rs.3.rs-662905/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-662905/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Remdesivir is the only small-molecule antiviral approved to date for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterized the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibited SARS-CoV-2, including variants of concern (VoC) in cell culture. Oral GS-621763 was efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduced SARS-CoV-2 burden to near-undetectable levels. When dosed therapeutically against VoC P.1 gamma (γ), oral GS-621763 blocked virus replication and prevented transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection. ","manuscriptTitle":"Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 and a variant of concern in ferrets","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-07-30 14:22:26","doi":"10.21203/rs.3.rs-662905/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"710bbaf2-bece-4648-9d0b-4eb529633cf3","owner":[],"postedDate":"July 30th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":6091586,"name":"Virology"}],"tags":[],"updatedAt":"2021-11-22T15:28:03+00:00","versionOfRecord":{"articleIdentity":"rs-662905","link":"https://doi.org/10.1038/s41467-021-26760-4","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2021-11-05 04:00:00","publishedOnDateReadable":"November 5th, 2021"},"versionCreatedAt":"2021-07-30 14:22:26","video":"","vorDoi":"10.1038/s41467-021-26760-4","vorDoiUrl":"https://doi.org/10.1038/s41467-021-26760-4","workflowStages":[]},"version":"v1","identity":"rs-662905","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-662905","identity":"rs-662905","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}