Multivalent, stabilized mannose-6-phosphates for the targeted delivery of toll-like receptor ligands and peptide antigens
| Autor: | Toroa McGlinn, Gijsbert A. van der Marel, Elena Tondini, Nico J. Meeuwenoord, Ferry Ossendorp, Dmitri V. Filippov, Niels R. M. Reintjens, Jeroen D. C. Codée, Herman S. Overkleeft, Tim P Hogervorst, Christopher A. Vis |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Endosome
Antigen presentation Mannose Peptide 010402 general chemistry Ligands 01 natural sciences Biochemistry chemistry.chemical_compound C-glycoside TLR ligands Antigen Adjuvanticity mannose-6-phosphate receptor Peptide synthesis Humans peptide conjugates Antigens Molecular Biology chemistry.chemical_classification Mannosephosphates Full Paper Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Toll-Like Receptors Full Papers 0104 chemical sciences Cell biology Amino acid solid-phase peptide synthesis Molecular Medicine Peptides |
| Zdroj: | ChemBioChem, 22(2), 434-440. WILEY-V C H VERLAG GMBH Chembiochem ChemBioChem, 22(2), 434-440 ChemBioChem |
| DOI: | 10.1002/cbic.202000538 |
| Popis: | Mannose‐6‐phosphate (M6P) is recognized by the mannose‐6‐phosphate receptor and plays an important role in the transport of cargo to the endosomes, making it an attractive tool to improve endosomal trafficking of vaccines. We describe herein the assembly of peptide antigen conjugates carrying clusters of mannose‐6‐C‐phosphonates (M6Po). The M6Po's are stable M6P mimics that are resistant to cleavage of the phosphate group by endogenous phosphatases. Two different strategies for the incorporation of the M6Po clusters in the conjugate have been developed: the first relies on a “post‐assembly” click approach employing an M6Po bearing an alkyne functionality; the second hinges on an M6Po C‐glycoside amino acid building block that can be used in solid‐phase peptide synthesis. The generated conjugates were further equipped with a TLR7 ligand to stimulate dendritic cell (DC) maturation. While antigen presentation is hindered by the presence of the M6Po clusters, the incorporation of the M6Po clusters leads to increased activation of DCs, thus demonstrating their potential in improving vaccine adjuvanticity by intraendosomally active TLR ligands. Enhancing the immune response: Two mannose‐6‐C‐phosphonate (M6Po) building blocks have been synthesized that can be incorporated into a conjugate by a “post‐assembly” click or an online SPPS approach to improve endosomal trafficking of vaccines. The generated M6Po conjugates, which were also equipped with a TLR7 ligand, were able to enhance the immune response by activation and maturation of dendritic cells. |
| Databáze: | OpenAIRE |
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