Facchini_et_al_2021.pdf (4.27 MB)
Synthetic Glycolipids as Molecular Vaccine Adjuvants: Mechanism of Action in Human Cells and In Vivo Activity
journal contribution
posted on 2023-07-26, 15:31 authored by Fabio A. Facchini, Alberto Minotti, Andrea Luraghi, Alessio Romerio, Nicole Gotri, Alejandra Matamoros-Recio, Andrea Iannucci, Charys Palmer, Guanbo Wang, Rebecca Ingram, Sonsoles Martin-Santamaria, Grisha Pirianov, Marco De Andrea, Miguel A. Valvano, Francesco PeriModern adjuvants for vaccine formulations are immunostimulating agents whose action is based on the activation of pattern recognition receptors (PRRs) by well-defined ligands to boost innate and adaptive immune responses. Monophosphoryl lipid A (MPLA), a detoxified analogue of lipid A, is a clinically approved adjuvant that stimulates toll-like receptor 4 (TLR4). The synthesis of MPLA poses manufacturing and quality assessment challenges. Bridging this gap, we report here the development and preclinical testing of chemically simplified TLR4 agonists that could sustainably be produced in high purity and on a large scale. Underpinned by computational and biological experiments, we show that synthetic monosaccharide-based molecules (FP compounds) bind to the TLR4/MD-2 dimer with submicromolar affinities stabilizing the active receptor conformation. This results in the activation of MyD88- and TRIF-dependent TLR4 signaling and the NLRP3 inflammasome. FP compounds lack in vivo toxicity and exhibit adjuvant activity by stimulating antibody responses with a potency comparable to MPLA.
History
Refereed
- Yes
Volume
64Issue number
16Page range
12261-12272Publication title
Journal of Medicinal ChemistryISSN
1520-4804External DOI
Publisher
American Chemical SocietyFile version
- Published version
Language
- eng
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Legacy posted date
2021-09-21Legacy creation date
2021-09-21Legacy Faculty/School/Department
Faculty of Science & EngineeringUsage metrics
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