Development of Efficient Covalent Inactivators of a Fungal Aspartate Semialdehyde Dehydrogenase.

Aspartate semialdehyde dehydrogenase (ASADH) catalyzes the second step in the fungal pathway towards the synthesis of threonine, isoleucine, and methionine, and it has been identified as a viable target for antifungal drug development. Our previous work produced a group of vinyl sulfones that function as irreversible covalent inactivators of this enzyme. We have now expanded this initial set to produce vinyl sulfones with higher kinetic efficiency as covalent inactivators of ASADH purified from the pathogenic fungal species Candida albicans. The catalytic efficiency of these inactivators has also been compared to related classes of irreversible inactivators, vinyl sulfonamides, acrylamides, and sulfonyl ketones.