Chemoenzymatic Synthesis
of <i>O</i>-Mannosylpeptides
in Solution and on Solid Phase
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Abstract
<i>O</i>-Mannosyl glycans are known to play
an important
role in regulating the function of α-dystroglycan (α-DG),
as defective glycosylation is associated with various phenotypes of
congenital muscular dystrophy. Despite the well-established biological
significance of these glycans, questions regarding their precise molecular
function remain unanswered. Further biological investigation will
require synthetic methods for the generation of pure samples of homogeneous
glycopeptides with diverse sequences. Here we describe the first total
syntheses of glycopeptides containing the tetrasaccharide NeuNAcα2-3Galβ1-4GlcNAcβ1-2Manα,
which is reported to be the most abundant <i>O</i>-mannosyl
glycan on α-DG. Our approach is based on biomimetic stepwise
assembly from the reducing end and also gives access to the naturally
occurring mono-, di-, and trisaccharide substructures. In addition
to the total synthesis, we have developed a “one-pot”
enzymatic cascade leading to the rapid synthesis of the target tetrasaccharide.
Finally, solid-phase synthesis of the desired glycopeptides directly
on a gold microarray platform is described