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Multivalent, Stabilized Mannose‐6‐Phosphates for the Targeted Delivery of Toll‐Like Receptor Ligands and Peptide Antigens
Author(s) -
Reintjens Niels R. M.,
Tondini Elena,
Vis Christopher,
McGlinn Toroa,
Meeuwenoord Nico J.,
Hogervorst Tim P.,
Overkleeft Herman S.,
Filippov Dmitri V.,
Marel Gijsbert A.,
Ossendorp Ferry,
Codée Jeroen D. C.
Publication year - 2021
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202000538
Subject(s) - mannose , endosome , mannose receptor , chemistry , peptide , conjugate , ligand (biochemistry) , glycosylation , phosphatase , mannose 6 phosphate , biochemistry , glycan , receptor , glycoprotein , microbiology and biotechnology , phosphorylation , biology , mathematical analysis , mathematics , growth factor , macrophage , in vitro
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.