A novel PLpro inhibitor scaffold that protects mice from Long-COVID

A novel PLpro inhibitor scaffold that protects mice from Long-COVID | 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 A novel PLpro inhibitor scaffold that protects mice from Long-COVID David Komander, Marcel Doerflinger, Stefanie M. Bader, Dale Calleja, and 38 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4899442/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has highlighted the vulnerability of a globally connected population to zoonotic viruses. The only FDA-approved coronavirus antiviral, Paxlovid, targets the essential SARS-CoV-2 main protease, Mpro. Whilst effective in the acute phase of an infection, Paxlovid cannot be used by all patients, can lead to viral recurrence, and does not protect against post-acute sequelae of COVID-19 (PASC), commonly known as Long COVID, an emerging significant health burden that remains poorly understood and untreated. Alternative antivirals that are addressing broader patient needs are urgently required. We here report our drug discovery efforts to target PLpro, a further essential coronaviral protease, for which we report a novel chemical scaffold that targets SARS-CoV-2 PLpro with low nanomolar activity, and which exhibits activity against PLpro of other pathogenic coronaviruses. Our lead compound shows excellent in vivo efficacy in a mouse model of severe acute disease. Importantly, our mouse model recapitulates long-term pathologies matching closely those seen in PASC patients, including lung, heart, gut and brain dysfunction. Our lead compound offers protection against PASC in this model, prevents lung pathology and reduces brain dysfunction, providing a potential treatment option for PASC sufferers going forward. Biological sciences/Biochemistry/Structural biology/X-ray crystallography/Nanocrystallography Biological sciences/Drug discovery/Medicinal chemistry/Structure-based drug design Biological sciences/Microbiology/Virology/SARS-CoV-2 Biological sciences/Immunology/Infectious diseases/Viral infection Full Text Additional Declarations Yes there is potential Competing Interest. This work is protected under provisional patent AU2024900559. DK is founder, shareholder and SAB member of Entact Bio and Proxima Bio. Supplementary Files Supplementaryuncroppedgel.pdf Supplement - uncropped gel PLproSupplementaryInformation.pdf Chemistry Supplement PLproExtData.pdf Extended Data Cite Share Download PDF Status: Under Review 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-4899442","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":340387933,"identity":"df9dda90-6488-4bd9-ba17-7a32e75406ae","order_by":0,"name":"David Komander","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsUlEQVRIiWNgGAWjYDCCM8wHGBgbJICsBKK1sCWQrIXHAKiFgQQtfGfOfJP4uMOCgZ89x4DhZxsRWiTP9m6TnHlGgkGy540BYy8xWgzO8267zdsmwWBwA2gLL3FaeJ7d/gvUYg/UwviXKC1ne9huM4JskcgxYCbKFskzx8x/9rZJ8EiceVZwWOYcEVr4ziQ/NvjZVifH35688eGbMiK0wAAPiDhAgoZRMApGwSgYBfgAAMtyNrQLlKs0AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-8092-4320","institution":"The Walter and Eliza Hall Institute of Medical Research","correspondingAuthor":true,"prefix":"","firstName":"David","middleName":"","lastName":"Komander","suffix":""},{"id":340387934,"identity":"7fab35bb-6eb8-4855-a5d1-2247bf9d9b04","order_by":1,"name":"Marcel Doerflinger","email":"","orcid":"https://orcid.org/0000-0001-9159-3021","institution":"Walter and Eliza Hall Institute","correspondingAuthor":false,"prefix":"","firstName":"Marcel","middleName":"","lastName":"Doerflinger","suffix":""},{"id":340387935,"identity":"99709697-92c3-41f7-954e-5b63e35f3658","order_by":2,"name":"Stefanie M. 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Long-COVID","fulltext":[],"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":true,"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":"","lastPublishedDoi":"10.21203/rs.3.rs-4899442/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4899442/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has highlighted the vulnerability of a globally connected population to zoonotic viruses. The only FDA-approved coronavirus antiviral, Paxlovid, targets the essential SARS-CoV-2 main protease, Mpro. Whilst effective in the acute phase of an infection, Paxlovid cannot be used by all patients, can lead to viral recurrence, and does not protect against post-acute sequelae of COVID-19 (PASC), commonly known as Long COVID, an emerging significant health burden that remains poorly understood and untreated. Alternative antivirals that are addressing broader patient needs are urgently required. \r\nWe here report our drug discovery efforts to target PLpro, a further essential coronaviral protease, for which we report a novel chemical scaffold that targets SARS-CoV-2 PLpro with low nanomolar activity, and which exhibits activity against PLpro of other pathogenic coronaviruses. Our lead compound shows excellent in vivo efficacy in a mouse model of severe acute disease. Importantly, our mouse model recapitulates long-term pathologies matching closely those seen in PASC patients, including lung, heart, gut and brain dysfunction. Our lead compound offers protection against PASC in this model, prevents lung pathology and reduces brain dysfunction, providing a potential treatment option for PASC sufferers going forward.","manuscriptTitle":"A novel PLpro inhibitor scaffold that protects mice from Long-COVID","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-21 03:22:20","doi":"10.21203/rs.3.rs-4899442/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":"d5c456a3-6ee1-4a3d-9cfe-f5c4738691d7","owner":[],"postedDate":"October 21st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":36064641,"name":"Biological sciences/Biochemistry/Structural biology/X-ray crystallography/Nanocrystallography"},{"id":36064642,"name":"Biological sciences/Drug discovery/Medicinal chemistry/Structure-based drug design"},{"id":36064643,"name":"Biological sciences/Microbiology/Virology/SARS-CoV-2"},{"id":36064644,"name":"Biological sciences/Immunology/Infectious diseases/Viral infection"}],"tags":[],"updatedAt":"2025-01-02T13:35:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-21 03:22:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4899442","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4899442","identity":"rs-4899442","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}