Marta Artola Perez de Azanza

Cyclic Sulfates and Sulfamidates: Versatile Chemical Functionalities for Targeting Glycosidases

Glycosyl hydrolases (GHs), the enzymes responsible for the cleavage of glycosidic bonds within complex carbohydrates, are pivotal enzymes involved in both health and disease. In biomedical research, selectively inhibiting specific GHs is vital for developing precise therapeutic strategies related to carbohydrate metabolism disorders. GH substrates traverse various conformational states to adapt to the steric and electronic properties, and mimicking these conformational transitions has proven to be highly effective in the creation of selective inhibitors for various glycosidases. For example, covalent nanomolar inhibitors for α-glucosidases have been developed using 1,6-cis-cyclic sulfate electrophiles, which mimic the 4C1 initial Michaelis complex conformation (Figure 1).¹ A similar approach involving the introduction of a nitrogen atom linked to the pseudo-anomeric position resulted in 1,6-cis-cyclic sulfamidates functioning as selective competitive inhibitors for α-galactosidases² or α-glucosidases³, contingent on their respective configurations. More recently, we have developed 1,6-trans-cyclic sulfates and sulfamidates exhibiting a flipped 1C4 chair conformation. Since inverting GH47-α-mannosidases follow a unusual 3S1 (Michaelis complex) → 3H4 (transition state) → 1C4 (product) conformational itinerary, mannose-configured 1,6-trans-cyclic sulfamidate has shown to target GH47-α-mannosidases by virtue of their 1C4 chair conformation mimicry with the product state. This rational design, has ultimately lead to new selective inhibitors for GH47-α-Mannosidases through a “bump and hole” strategy.⁴

References:
1- M. Artola et al., ACS Cent. Sci. 2017, (3) 784–793.
2- M. Artola et. al. Chem. Sci. 2019, (10) 9233-9243.
3- K. Kok et al. J. Am. Chem. Soc. 2022, (20144) 14819–14827.
4- A. Males et al. Chem. Sci. 2023, 10.1039/d3sc05016e.