Discovery of hALPL Agonists for Osteogenesis from A Selenium-containing DNA-encoded Natural Product Library

Discovery of hALPL Agonists for Osteogenesis from A Selenium-containing DNA-encoded Natural Product Library | 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 Discovery of hALPL Agonists for Osteogenesis from A Selenium-containing DNA-encoded Natural Product Library Peixiang Ma, Shuning Zhang, Hang Zhang, Wanting Bi, Shaoneng Hou, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7459537/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 Tissue-nonspecific alkaline phosphatase (hALPL) deficiency or dysfunction is a key driver of bone developmental abnormalities. However, no small-molecule agonists are available for the therapeutic target hALPL—particularly its pathogenic mutants. We bridge this gap by developing an antibody maturation-inspired chemical maturation strategy that integrates DNA-encoded library (DEL) selection with parallel synthesis for rapid functional chemical discovery. Using a selenium-containing DNA-encoded natural product library (Se-nDEL), comprising 25900 selenium-containing derivatives and affinity-based selection, we identified hALPL-binding candidates. The candidates were further functionally matured via selenium-nitrogen exchange (SeNEx) chemistry-enabled in situ nanomole-scale parallel synthesis. These efforts culminated in the identification of E7, the first small-molecule hALPL agonist, which directly binds to and activates hALPL, thereby promoting osteogenesis both in vitro and in vivo. Notably, E7 demonstrated the ability to restore the enzymatic activities of seven pathogenic mutations, further highlighting its therapeutic potential. Our work establishes a scalable platform for agonist development, combining DEL-driven hit discovery with parallel synthesis for functional optimization, with broad applicability to challenging targets in bone biology and beyond. Physical sciences/Chemistry/Chemical synthesis Physical sciences/Chemistry/Organic chemistry DNA-encoded library selenium-nitrogen exchange (SeNEx) functional maturation Osteogenesis ALPL Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupportingInformationNBE.pdf Supporting Information 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. 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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-7459537","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":508951089,"identity":"b5d6c918-10dc-4695-9eee-ea076d2ff524","order_by":0,"name":"Peixiang 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