What’s not to love about covalent inhibitors? Well,
unfortunately, quite a bit when you start thinking about it. Reversible
inhibitors offer an extra layer of subtlety, they are tuneable, time-dependent and can modulate individual functions of
proteins or biological systems by using several inhibitors in combination. That is as
long as you can make them potent and selective enough; covalent inhibitors tend
to solve the first problem in spades, once you make your covalent bond it’s
staying there usually knocking out the enzyme target. Yet the greatest strength
is the greatest weakness, unfortunately by improving the potency of your
compounds the problems with selectivity are multiplied. If your covalent
inhibitor goes to the wrong protein first well tough; this great if you’re a
beta-lactam antibiotic trying to kill a bacterium, but killing things isn't what tool compounds are for.
But what if you could make a reversible covalent inhibitor?
Potentially you could gain the potency and, if well designed, the selectivity
as well. Maybe this would still be difficult to incorporate into a drug, but as
a basis for a sophisticated tool compound it could be extremely useful. Taunten et.al. have developed such a system that targets the amino acid cysteine.
