Chemical modification of pyrroloquinoline quinone identifies a monomethyl ester derivative that enhances DUOX activation and causes lethality in C. elegans

Chemical modification of pyrroloquinoline quinone identifies a monomethyl ester derivative that enhances DUOX activation and causes lethality in C. elegans | 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 Article Chemical modification of pyrroloquinoline quinone identifies a monomethyl ester derivative that enhances DUOX activation and causes lethality in C. elegans Hiroyuki Sasakura, Moribe Hiroki, Kazuto Ikemoto, Masashi Ikeno, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9310397/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Pyrroloquinoline quinone (PQQ) is a multifunctional natural coenzyme that plays important roles in innate immunity, nutritional physiology, and redox biology, including the activation of dual oxidases (DUOXs). Although native PQQ has been extensively studied, the biological consequences of its chemical modification remain poorly understood. Here, we synthesized several PQQ derivatives and identified PQQMe, a monomethyl ester derivative that activates DUOX more potently than native PQQ, even at low concentrations. PQQMe induced rapid lethality in C. elegans , as well as internal hatching resulting from severe defects in the egg-laying apparatus, a phenotype that occurred independently of DUOX. This outcome contrasted sharply with the lifespan-extending effects observed with native PQQ and its prodrug derivative, the acetone adduct ACTPQQ, indicating that esterification profoundly reshapes the biological activity spectrum of PQQ. Despite its pronounced biological effects, PQQMe exhibited greater tolerability than PQQ in mammalian cells and mice. Together, these findings identify PQQMe as a chemically modified PQQ derivative that enhances DUOX activation and induces a distinct lethal phenotype in C. elegans , suggesting that chemical modification of a multifunctional coenzyme is a useful strategy for inducing new biological functions. Biological sciences/Biochemistry Biological sciences/Chemical biology Pyrroloquinoline quinone (PQQ) chemical modification monomethyl ester dual oxidase (DUOX) reactive oxygen species Caenorhabditis elegans Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 19 May, 2026 Reviewers agreed at journal 08 May, 2026 Reviews received at journal 22 Apr, 2026 Reviewers agreed at journal 16 Apr, 2026 Reviewers invited by journal 16 Apr, 2026 Editor assigned by journal 16 Apr, 2026 Editor invited by journal 15 Apr, 2026 Submission checks completed at journal 10 Apr, 2026 First submitted to journal 10 Apr, 2026 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. 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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-9310397","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":626282411,"identity":"c2e15f93-df33-4d34-abd6-6590548a5abd","order_by":0,"name":"Hiroyuki Sasakura","email":"data:image/png;base64,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","orcid":"","institution":"Fujita Health University","correspondingAuthor":true,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Sasakura","suffix":""},{"id":626282415,"identity":"0b8d39b2-3818-425e-bfd8-2c92f9003f0d","order_by":1,"name":"Moribe Hiroki","email":"","orcid":"","institution":"Kurume University","correspondingAuthor":false,"prefix":"","firstName":"Moribe","middleName":"","lastName":"Hiroki","suffix":""},{"id":626282419,"identity":"4c330d9d-7c54-4891-80d1-5707075c5c5d","order_by":2,"name":"Kazuto Ikemoto","email":"","orcid":"","institution":"Mitsubishi Gas Chemical Company, Inc. 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Although native PQQ has been extensively studied, the biological consequences of its chemical modification remain poorly understood. Here, we synthesized several PQQ derivatives and identified PQQMe, a monomethyl ester derivative that activates DUOX more potently than native PQQ, even at low concentrations. PQQMe induced rapid lethality in \u003cem\u003eC. elegans\u003c/em\u003e, as well as internal hatching resulting from severe defects in the egg-laying apparatus, a phenotype that occurred independently of DUOX. This outcome contrasted sharply with the lifespan-extending effects observed with native PQQ and its prodrug derivative, the acetone adduct ACTPQQ, indicating that esterification profoundly reshapes the biological activity spectrum of PQQ. Despite its pronounced biological effects, PQQMe exhibited greater tolerability than PQQ in mammalian cells and mice. 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