{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T18:14:41Z","timestamp":1764785681728,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases","award":["PE00000007"],"award-info":[{"award-number":["PE00000007"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["675671"],"award-info":[{"award-number":["675671"]}]},{"name":"Next Generation EU \u201cMissione 4\u2014Componente 1-CUP","award":["G53D23003320006"],"award-info":[{"award-number":["G53D23003320006"]}]},{"name":"University of Milan Research Grant PSR2025","award":["PSR2025_DIP_005_MCIVE"],"award-info":[{"award-number":["PSR2025_DIP_005_MCIVE"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Molecules"],"abstract":"<jats:p>Bacteroides fragilis, a prominent commensal of the human gut microbiota, plays a vital role in immune system regulation through its capsular polysaccharide A (PSA), which requires a glycolipid anchor structurally reminiscent of lipid A. While canonical Escherichia coli lipid A acts as a potent TLR4 agonist contributing to septic shock and inflammatory disorders, certain B. fragilis-derived glycolipids demonstrate antagonistic effects, offering potential as anti-inflammatory agents. In this study, we report the synthesis and preliminary computational evaluation of a library of glycolipids inspired by B. fragilis lipid A. Three lipid As, including a tetra-acylated 1-phosphoryl lipid A analog (Tetra C-1), were synthesized and assessed using molecular docking simulations targeting the human TLR4\/MD-2 complex. Docking results reveal that Tetra C-1 exhibits more favorable antagonist binding characteristics compared to the well-studied TLR4 antagonist Eritoran. This work highlights a microbiota-informed strategy for the development of novel TLR4 antagonists, potentially enabling targeted modulation of innate immunity for therapeutic applications in inflammatory diseases and as vaccine adjuvants.<\/jats:p>","DOI":"10.3390\/molecules30193927","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T08:21:51Z","timestamp":1759220511000},"page":"3927","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis and Docking Studies of Glycolipids Inspired by Bacteroides fragilis Lipid A"],"prefix":"10.3390","volume":"30","author":[{"given":"Davie","family":"Kenneth","sequence":"first","affiliation":[{"name":"Department of Chemistry, Universit\u00e0 degli Studi di Milano, Via C. Golgi 19, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0040-258X","authenticated-orcid":false,"given":"Cristina Manuela","family":"Santi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Universit\u00e0 degli Studi di Milano, Via C. Golgi 19, 20133 Milan, Italy"},{"name":"Laboratory for Polymers and Biomaterials, Fondazione Istituto Italiano di Tecnologia, 16163 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7748-3375","authenticated-orcid":false,"given":"Francesca","family":"Tanda","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Universit\u00e0 degli Studi di Milano, Via C. Golgi 19, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"Izzo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Universit\u00e0 degli Studi di Milano, Via C. Golgi 19, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5171-1062","authenticated-orcid":false,"given":"Monica","family":"Civera","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Universit\u00e0 degli Studi di Milano, Via C. Golgi 19, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4101-2908","authenticated-orcid":false,"given":"Giuseppe","family":"D\u2019Orazio","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Universit\u00e0 degli Studi di Milano, Via C. 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