2. Academic Validation
  3. New Glucosamine-Based TLR4 Agonists: Design, Synthesis, Mechanism of Action, and In Vivo Activity as Vaccine Adjuvants

New Glucosamine-Based TLR4 Agonists: Design, Synthesis, Mechanism of Action, and In Vivo Activity as Vaccine Adjuvants

  • J Med Chem. 2023 Feb 23;66(4):3010-3029. doi: 10.1021/acs.jmedchem.2c01998.
Alessio Romerio 1,  Nicole Gotri 1,  Ana Rita Franco 1,  Valentina Artusa 1,  Mohammed Monsoor Shaik 1,  Samuel T Pasco 2,  Unai Atxabal 2,  Alejandra Matamoros-Recio 3,  Marina Mínguez-Toral 3,  Juan Diego Zalamea 2,  Antonio Franconetti 2,  Nicola G A Abrescia 2 4,  Jesus Jimenez-Barbero 2 4 5 6,  Juan Anguita 2 4,  Sonsoles Martín-Santamaría 3,  Francesco Peri 1
Affiliations

Affiliations

  • 1 Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126 Milano, Italy.
  • 2 Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain.
  • 3 Centro de Investigaciones Biológicas Margarita Salas CSIC, C/Ramiro de Maeztu, 9, 28040 Madrid, Spain.
  • 4 Ikerbasque, Basque Foundation for Science, Plaza Euskadi 5, 48009 Bilbao, Bizkaia, Spain.
  • 5 Department of Organic Chemistry, II Faculty of Science and Technology, EHU-UPV, 48940 Leioa, Spain.
  • 6 Centro de Investigación Biomédica En Red de Enfermedades Respiratorias, 28029 Madrid, Spain.
PMID: 36728697 DOI: 10.1021/acs.jmedchem.2c01998
Abstract

We disclose here a panel of small-molecule TLR4 agonists (the FP20 series) whose structure is derived from previously developed TLR4 ligands (FP18 series). The new molecules have increased chemical stability and a shorter, more efficient, and scalable synthesis. The FP20 series showed selective activity as TLR4 agonists with a potency similar to FP18. Interestingly, despite the chemical similarity with the FP18 series, FP20 showed a different mechanism of action and immunofluorescence microscopy showed no NF-κB nor p-IRF-3 nuclear translocation but rather MAPK and NLRP3-dependent inflammasome activation. The computational studies related a 3D shape of FP20 series with agonist binding properties inside the MD-2 pocket. FP20 displayed a CMC value lower than 5 μM in water, and small unilamellar vesicle (SUV) formation was observed in the biological activity concentration range. FP20 showed no toxicity in mouse vaccination experiments with OVA antigen and induced IgG production, thus indicating a promising Adjuvant activity.

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