Tetrafluorination of sugars as strategy for enhancing protein-carbohydrate affinity: Application to UDP-galp mutase inhibition

Tetrafluorinated analogues of both UDP-galactopyranose and UDP-galactofuranose have been synthesized and assayed against UDP-galactopyranose mutase, a key enzyme for Mycobacterium tuberculosis cell wall biosynthesis. Competition assays and STD-NMR spectroscopy techniques have evidenced not only the first unambiguous case of affinity enhancement through local sugar polyfluorination, but also showed that tetrafluorination can still have a beneficial effect on binding when monofluorination at the same position does not. On all fours: Tetrafluorinated analogues of UDP-galactopyranose and UDP-galactofuranose were synthesized and assayed against UDP-galactopyranose mutase (UGM), a key enzyme in Mycobacterium tuberculosis cell wall biosynthesis. The tetrafluorinated sugar analogue was found to bind the enzyme more effectively than the unfluorinated natural substrate.