Vinyl sulfones: selective and tunable covalent warheads against challenging enzyme targets

Over the past several decades there has been a growing recognition of the role that covalent drug candidates have played in the drug development process. With this recognition, compounds that are capable of selectively and irreversibly inactivating their targets through covalent bond formation are now being specifically designed rather than being serendipitously identified. Until recently, vinyl sulfones comprised only a small fraction of the warheads under development as covalent drug candidates, but an increasing number of compounds containing this versatile functional group are now under development and consideration as drug candidates. Vinyl sulfones are generally more reactive than structurally-related acrylamides and vinyl sulfonamides, presenting a challenge for producing target-specific inactivators. The most progress in overcoming this challenge has been made in designing vinyl sulfones as selective inactivators of microbial and human cysteine proteases, incorporating these reactive warheads into peptide and peptide mimetic structures that utilize the substrate recognition motifs of these proteases. However, effective vinyl sulfones have also been produced against a growing range of phosphoryl-utilizing enzymes including kinases, phosphatases and metabolic enzymes. Here, target selection takes advantage of the capability of the sulfonyl group to act as a phosphoryl mimic. An example of this approach is presented for the targeting of a metabolic enzyme, fungal aspartate semialdehyde dehydrogenase, an essential microbial enzyme in amino acid metabolism. The studies conducted to date demonstrate the potential utility of designing vinyl sulfone drug candidates to achieve selectivity against challenging and new drug-resistant targets.