Biomedical Engineering Reference
In-Depth Information
(Figure 12). A tetramer glycopeptide antigen
32
, consisting of the 16 amino acids
tandem repeat of mucin MUC4 was prepared using a peptide synthesizer on a
Tentagel resin bearing a lysine core through a Wang linker and with the Fmoc-
ThrGalNAc building block. The glycopeptide
32
was obtained in 68% yield after
acidic cleavage and HPLC purification. This strategy was further extended to
prepare a more complex octameric MUC1 tandem repeat glycopeptide with
similar success.
A simpler model based on a single lysine core was also proposed (Figure
13). In this study, oxime chemoselective ligation was used for the convergent
assembly of a multiantigenic tri-branched glycopeptide mimicking the MUC1
glycoprotein and containing the universal Pan DR (PADRE) T helper epitope
[59]. In this study, the authors first prepared two MUC1 repeat units
33
-
34
containing either the Tn or T antigen on the threonine residue, and an aminooxy
acetic acid linker at
N
-terminal end (Figure 13). The PADRE peptide epitope
35
was next synthesized in line with a MUC1 repeat unit bearing a Lys-Ala
dipeptide at the
C
-terminal end. The lysine side chain was used for incorporation
of a serine residue as masked aldehyde whereas a protected aldehyde was
introduced during the peptide cleavage by aminolysis with aminoacetaldehyde-
dimethylacetal [60]. After successive aldehyde formations and oxime ligations,
the final multiantigenic MUC1 glycopeptide
36
was obtained and evaluated in
mice. Immunological assays showed that their construction induce antibodies
that recognized native MUC1 expressed on human breast tumors.
OM e
O
H
N
H
N
a-A-K-Cha-V-A-A-W-T-L-K-A-a-P-P-A-H-G-V-T-S-A-P-D-T-R-P-A -P-G-S-T-A
N
H
OMe
35
O
O
OH
O
HO
HO
33
O
OH
O
H
2
N
AcH N
O
P-P-A-H-G-V-T-S-P-D-T-R-P-A-P-G-S-T-A
H 2N
OH
OH
H O
HO
H O
O
34
O
O
O
OH
A cHN
O
H 2N
P-P-A-H-G-V-T-S-P-D-T-R-P-A-P-G-S-T-A
OH
OH
H O
HO
H O
O
O
O
O
O
H
N
H
N
a-A-K-Cha-V-A-A-W-T-L-K-A-a-P-P-A-H-G-V-T-S-A-P-D-T-R-P-A -P-G-S-T-A
OH
A cHN
O
P-P-A-H-G-V-T-S-P-D-T-R-P-A-P-G-S-T-A
N
H
N
PADRE
MUC1
O
O
MUC1-TF
36
OH
HO
HO
O
O
O
AcH N
O
P-P-A-H-G-V-T-S-P-D-T-R-P-A-P-G-S-T-A
N
MUC1-Tn
Fig. 13. Oxime assembly of multiantigenic vaccines candidates based a single lysine core.
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