Abstract
Covalent linking of immunogenic oligopeptides with synthetic Toll-like receptor ligands is a useful approach to develop self-adjuvanting vaccines. In particular, small-molecule based agonists of Toll-like receptor 7 (TLR7) that are derived from 8-oxo-adenine core are potentially promising because these chemically robust TLR7 ligands can be connected to peptide T-cell epitopes via straightforward solid-phase peptide synthesis. In this contribution we present the synthesis of a Boc-protected 9-benzyl-2-alkoxy-8-oxo-adenine building block and its application in the online solid phase synthesis of three peptide conjugates that differ in the position of the TLR7 ligand within the peptide. The conjugates are able to induce dendritic cell maturation and T cell proliferation while the position of the ligand impacts T cell proliferation potency.
Highlights
Covalent linking of immunogenic oligopeptides with synthetic Toll-like receptor ligands is a useful approach to develop self-adjuvanting vaccines
Toll-like receptors (TLRs) are part of the mammalian innate immune system that forms the first line of defence against pathogens by recognising pathogen associated molecular patterns (PAMPs).[1]
TLR9 recognizes bacterial and viral single stranded DNA, the latter is recognized by Toll-like receptor 7 (TLR7).5,6 As modulators of the immune system TLR ligands are important drug targets and much research has been directed to the development of small-molecule TLR agonists.[7]
Summary
Covalent linking of immunogenic oligopeptides with synthetic Toll-like receptor ligands is a useful approach to develop self-adjuvanting vaccines. Several of these conjugates exhibit improved immunological properties in comparison with a mixture of the composing components.[18,19,20] Such conjugates in which a TLR7 ligand is covalently connected to an antigenic peptide have been prepared as well. The position in the TLR7 agonist to which the peptide epitope is connected proved to be of prime importance for the immunological activity of the resulting conjugate: Jin and co-workers revealed that attachment of the 8-hydroxyadenine based TLR7 agonist
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