What are the disadvantages of covalent inhibitors?

Covalent inhibitors are chemicals that form a covalent bond with their target proteins, usually modifying them irreversibly and causing them to lose their function. This can have advantages and disadvantages.

The same characteristics that give covalent inhibitors their many advantages as promising therapeutics can also create challenges when developing drugs. 

Because of the irreversible, permanent nature of the binding, any binding must necessarily be selective. In case of insufficiently selective binding, the drug or chemical may bind to unintended proteins. This could lead to inadvertent, off-target effects that could potentially result in long-term damage. 

Another disadvantage of covalent inhibitors is the possibility that some target proteins may undergo structural modifications or mutate. These structural changes prevent the drug from effectively binding and inhibiting the protein, which reduces the chemical’s long-term efficacy and may also lead to development of resistance.