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Título: | Serine-/Cysteine-Based sp2-Iminoglycolipids as Novel TLR4 Agonists: Evaluation of Their Adjuvancy and Immunotherapeutic Properties in a Murine Model of Asthma |
Autor: | González-Cuesta, Manuel; Lai, Alan Chuan-Ying; Chi, Po-Yu; Hsu, I-Ling; Liu, Nien-Tzu; Wu, Ko-Chien; García Fernández, José M; Chang, Ya-Jen; Ortiz Mellet, Carmen | Palabras clave: | Serine-/Cysteine-Based sp2 Iminoglycolipids TLR4 Agonists Adjuvancy Immunotherapeutic Murine Model Asthma |
Fecha de publicación: | 13-abr-2023 | Editor: | ACS Publications | Citación: | Journal of Medicinal Chemistry 66(7):4273-5304 (2023) | Resumen: | Glycolipids with TLR4 agonistic properties can serve either as therapeutic agents or as vaccine adjuvants by stimulating the development of proinflammatory responses. Translating them to the clinical setting is hampered by synthetic difficulties, the lack of stability in biological media, and/or a suboptimal profile of balanced immune mediator secretion. Here, we show that replacement of the sugar fragment by an sp2-iminosugar moiety in a prototypic TLR4 agonist, CCL-34, yields iminoglycolipid analogues that retain or improve their biological activity in vitro and in vivo and can be accessed through scalable protocols with total stereoselectivity. Their adjuvant potential is manifested in their ability to induce the secretion of proinflammatory cytokines, prime the maturation of dendritic cells, and promote the proliferation of CD8+ T cells, pertaining to a Th1-biased profile. Additionally, their therapeutic potential for the treatment of asthma, a Th2-dominated inflammatory pathology, has been confirmed in an ovalbumin-induced airway hyperreactivity mouse model. | Versión del editor: | https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.2c01948 | URI: | http://hdl.handle.net/10261/355110 | DOI: | 10.1021/acs.jmedchem.2c01948 | ISSN: | 0022-2623 |
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