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N
N
Lipopeptide
(a)
MUC1
N
N
N
MUC1
N
(b)
Lipopeptide
N
N
MUC1
N
N
N
MUC1
N
N
N
MUC1
N
(c)
Lipopeptide
N
N
MUC1
N
N
N
MUC1
N
FIGURE 13.2
Structure of the mono-, di-, and tetravalent MUC1 glycopeptide conjugates
with the TLR2 lipopeptide ligand. (a) monovalent; (b) divalent; (c) tetravalent.
epithelial tissues and are highly overexpressed on tumor cells [32]. On the other
hand, tripalmitoyl-(S)-glycerylcysteine lipopeptides, such as Pam
3
CysSer-(Lys)
4
(Pam
3
CSK
4
) derived from bacterial lipopeptides, are toll-like receptor 2 (TLR2)
ligands and have shown capacity to act as strong B lymphocyte and macrophage
activators [35]. In this way, they can be used as immune stimulants in synthetic
vaccines, besides the fact of having much fewer side effects if compared with pro-
tein conjugates. In this context, a different approach involving the conjugation of
MUC1-derived glycopeptides to Pam
3
CysSer-(Lys)
4
(Pam
3
CSK
4
) lipopeptides by
1,3-dipolar cycloaddition reaction was applied with the aim to get potential antitumor
vaccines able to elicit a strong humoral immune response (Fig. 13.2). For this pur-
pose, four glycopeptides (
46-49
) differing in the tumor-carbohydrate antigens (Tn or
T) attached to the MUC1 peptide sequence were firstly synthesized under established
SPS conditions, followed by coupling of their N-terminus to a spacer functionalized
with an azido group [36] (Scheme 13.8). Regarding Pam
3
CSK
4
lipopeptides, distinct
mono-, di-, and tetra-alkyne functionalized TLR ligand lipopeptides were prepared
by means of suitably designed multilysine cores assembly with subsequent coupling
of the alkyne-functionalized spacer. Finally, copper(I)-mediated click reactions for
conjugation of glycopeptides with the TLR ligand lipopeptides were carried out in
the presence of Cu(OAc)
2
and sodium ascorbate as catalytic system, in water at
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