1. Synthetic Glycolipids as Molecular Vaccine Adjuvants: Mechanism of Action in Human Cells and In Vivo Activity
- Author
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Nicole Gotri, Fabio A. Facchini, Alberto Minotti, Guanbo Wang, Grisha Pirianov, Marco De Andrea, Miguel A. Valvano, Alessio Romerio, Francesco Peri, Rebecca J. Ingram, Alejandra Matamoros-Recio, Charys Palmer, Sonsoles Martín-Santamaría, Andrea Luraghi, Andrea Iannucci, European Commission, Ministero dell'Istruzione, dell'Università e della Ricerca, Ministerio de Ciencia e Innovación (España), Facchini, Fabio A., Minotti, Alberto, Luraghi, Andrea, Matamoros-Recio, Alejandra, Iannucci, Andrea, Wang, Guanbo, Ingram, Rebecca, Martín-Santamaría, Sonsoles, Pirianov, Grisha, De Andrea, Marco, Valvano, Miguel A., Peri, Francesco, Facchini, F, Minotti, A, Luraghi, A, Romerio, A, Gotri, N, Matamoros-Recio, A, Iannucci, A, Palmer, C, Wang, G, Ingram, R, Martin-Santamaria, S, Pirianov, G, De Andrea, M, Valvano, M, Peri, F, Facchini, Fabio A. [0000-0002-4339-5845], Minotti, Alberto [0000-0002-0443-6472], Luraghi, Andrea [0000-0002-9452-7561], Matamoros-Recio, Alejandra [0000-0003-1563-9408], Iannucci, Andrea [0000-0001-5194-8959], Wang, Guanbo [0000-0001-8210-8805], Ingram, Rebecca [0000-0003-1832-2457], Martín-Santamaría, Sonsoles [0000-0002-7679-0155], Pirianov, Grisha [0000-0002-6480-7765], De Andrea, Marco [0000-0002-3188-5783], Valvano, Miguel A. [0000-0001-8229-3641], and Peri, Francesco [0000-0002-3417-8224]
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Macrophage ,Inflammasomes ,medicine.medical_treatment ,Monophosphoryl Lipid A ,Glycolipid ,Article ,Inflammasome ,Lipid A ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Adjuvants, Immunologic ,SDG 3 - Good Health and Well-being ,In vivo ,NLR Family, Pyrin Domain-Containing 3 Protein ,Drug Discovery ,medicine ,Animals ,Humans ,030304 developmental biology ,Glucosamine ,0303 health sciences ,Animal ,Chemistry ,Macrophages ,Pattern recognition receptor ,3. Good health ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,Adaptor Proteins, Vesicular Transport ,Mechanism of action ,Biochemistry ,Myeloid Differentiation Factor 88 ,Molecular Medicine ,Female ,Glycolipids ,medicine.symptom ,Adjuvant ,Human ,Interleukin-1 ,Signal Transduction ,030215 immunology ,medicine.drug - Abstract
12 p.-7 fig.-1 schem.-1 graph. abst., Modern 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., The support from European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 860325 (www.BactiVax.eu), Italian Ministry grant PRIN 2017, no. 2017E44A9P (BacHounds:Supramolecular nanostructures for bacteria detection), and the Spanish Ministry for Science and Innovation (grants CTQ2017-88353-R and PRE2018-086249) is acknowledged.
- Published
- 2021