Artículo
Serine-/Cysteine-based sp2-Iminoglycolipids as novel TLR4 agonists: evaluation of their adjuvancy and immunotherapeutic properties in a murine model of asthma
Autor/es | González Cuesta, Manuel
Lai, Alan Chuan Ying Chi, Po Yu Hsu, I. Ling Liu, Nien Tzu Wu, Ko Chien García Fernández, José Manuel Ortiz Mellet, Carmen |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2023 |
Fecha de depósito | 2023-05-10 |
Publicado en |
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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 ... 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. |
Agencias financiadoras | Ministerio de Ciencia e Innovación (MICIN). España Agencia Estatal de Investigación. España Junta de Andalucía Gobierno de Taiwán |
Identificador del proyecto | PID2019-105858RB-I00
RTI2018- 097609-B-C21 PID2021-124247OB-C21 P20_00166 111-2320-B-001-025-MY3 |
Cita | González Cuesta, M., Lai, A.C.Y., Chi, P.Y., Hsu, I.L., Liu, N.T., Wu, K.C.,...,Ortiz Mellet, C. (2023). Serine-/Cysteine-based sp2-Iminoglycolipids as novel TLR4 agonists: evaluation of their adjuvancy and immunotherapeutic properties in a murine model of asthma. Journal of Medicinal Chemistry, 66 (7), 4768-4783. https://doi.org/10.1021/acs.jmedchem.2c01948. |
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acs.jmedchem.2c01948.pdf | 2.752Mb | [PDF] | Ver/ | |