Sulfur-and selenium-targeting warheads: Reaction-based design of electrophilic warheads for selective inhibition of enzyme

Abstract

Covalent inhibitors for nucleophilic residues, particularly cysteine (Cys) and selenocysteine (Sec), have resurfaced as precision therapies for modifying disease-associated enzymes. The main advantage of covalent inhibition is its ability to form a stable covalent bond with a particular residue near the binding site. Permanent alteration of Cys and Sec residues by covalent inhibitors is possible since the sulfur and selenium atoms have high chemical reactivities and intrinsic variations in the redox behaviors, which enable the rational design of covalent inhibitors targeting the Cys/Sec residues. Moreover, recent breakthroughs covering a wide range of warheads (reactive moieties of covalent inhibitors), from traditional thiol-selective motifs (e.g. acrylamides) to emerging selenol-selective analogs (e.g., Ebselen D, diacyl furoxan derivatives, etc.), exhibit the potent inhibition against kinases and redox-regulating enzymes having a thiol/selenol group in the active sites. Although we have comprehensively encountered numerous promising therapeutic potentials and preclinical data of Cys/Sec-targeted covalent inhibitors, there is still a room of challenges in attaining the precise Cys-/Sec-selectivity, reducing the warhead toxicity, and improving the in vivo stability. This mini-review combines recent insights and developments of thiol-and selenol-selective warheads within the midst of the intersection of chemical biology and medicinal chemistry. We also discuss future directions of the relevant research with the goal of improved safety and effectiveness.