In recent years chemical site-selective protein
modification has emerged as a powerful method to access and study homogeneous
post-translational modified proteins. We have developed a number of methodologies based on a tag-and-modify protein modification
strategy that provide a unique opportunity to introduce a fluorine atom at a
single designated amino acid residue [1]. Herein we describe the development of
complementary methods that allow the preparation of well-defined synthetic
fluorinated glycoproteins and importantly [18F]-radiolabelled glycoproteins. These methods
exploit (a) the copper-catalyzed Huisgen cycloaddition reaction that requires
the incorporation of homopropargyl glycine ‘tag’ into proteins prior to
modification with a bespoke sugar reagent, (b) the thiol disulfide or
diselenide exchange reaction with natural cysteine and finally (c) the
conjugate addition of fluoroglycosyl thiols to dehydroalanine (directly
accessible from Cys) that allow the straightforward
introduction of [18F]FDG, the most extensively used positron
emission topography (PET) radiotracer in nuclear medicine, into proteins without
the need for any protecting group chemistry. Finally, Endo A-catalyzed elongation of these
fluoroglycoproteins allows access to homogeneous, complex glycoproteins proving
that different unnatural linkages and sugar configurations can be tolerated [2]. This strategy allows the preparation of complex
fluorinated glycoproteins in two steps with no need to manipulate either the protein or the complex glycan for
F incorporation.
[1] (a) Boutureira, O.; Bernardes, G. J. L.; Fernández-González,
M.; Anthony, D. C.; Davis, B. G. Angew.
Chem. Int. Ed. 2012, 51, 1432. (b) Boutureira, O.; Bernardes, G. J. L.; D’Hooge, F.; Davis, B. G. Chem. Commun. 2011, 47, 10010. (c) Boutureira,
O.; D’Hooge, F.; Fernández-González, M.; Bernardes, G. J. L.; Sánchez-Navarro,
M.; Koeppe, J. R.; Davis, B. G. Chem.
Commun. 2010, 46, 8142.
[2] Fernández-González, M.; Boutureira, O.;
Bernardes, G. J. L.; Chalker, J. M.; Young, M. A.; Errey, J. C.; Davis, B. G. Chem.
Sci. 2010, 1, 709.
