Synthetic Glycolipids as Molecular Vaccine Adjuvants: Mechanism of Action in Human Cells and In Vivo Activity

Facchini, Fabio A., Minotti, Alberto, Luraghi, Andrea, Romerio, Alessio, Gotri, Nicole, Matamoros-Recio, Alejandra, Iannucci, Andrea, Palmer, Charys, Wang, Guanbo, Ingram, Rebecca, Martin-Santamaria, Sonsoles, Pirianov, Grisha, De Andrea, Marco, Valvano, Miguel A. and Peri, Francesco (2021) Synthetic Glycolipids as Molecular Vaccine Adjuvants: Mechanism of Action in Human Cells and In Vivo Activity. Journal of Medicinal Chemistry, 64 (16). pp. 12261-12272. ISSN 1520-4804

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Abstract

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.

Item Type:	Journal Article
Keywords:	Immunology, Lipids, Peptides and proteins, Biopolymers, Molecules
Faculty:	Faculty of Science & Engineering
Depositing User:	Lisa Blanshard
Date Deposited:	21 Sep 2021 15:51
Last Modified:	17 Jan 2022 15:23
URI:	https://arro.anglia.ac.uk/id/eprint/706951

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