Irreversible covalent drugs present numerous advantages over reversible non-covalent inhibitors.
- Longer-lasting effect as new target synthesis is needed for activity restoration.
- Effective inhibition of challenging targets like those with a shallow pocket or targets that engage in protein–protein interactions.
- Less frequent dosing.
- Higher selectivity by targeting poorly conserved amino acids (i.e. cysteines).
Despite their advantages, irreversible covalent drugs face challenges like off-target toxicities and immunogenic risks. Introducing reversibility can mitigate these issues, as reversible covalent inhibitors are not permanently bound, they can detach from unintended proteins, reducing the risk of immune system activation and off-target toxicity. By tuning the reactivity of the warhead (k3) and the residence time, reversible covalent inhibitors can maintain the benefits of irreversible covalent inhibitors while limiting off-target toxicity. One way to achieve this is adjusting the reactivity of the covalent warhead and making structural changes around it to stabilize the reversible covalent adduct and extend its duration.