Dethioacylation by Sirtuins 1–3: Considerations for Drug Design using Mechanism-based Sirtuin Inhibition

The sirtuin enzymes are potential drug targets for intervention in a series of diseases. Efforts to inhibit enzymes of this class with thioamide- and thiourea-containing, substrate-mimicking entities have produced a number of high-affinity binders. However, less attention has been dedicated to the investigation of the stability of these inhibitors under various conditions. Here, we provide evidence of unprecedented degree of cleavage of short-chain epsilon-N-thioacyllysine modifications meant to target these sirtuins and further provide insights into the serum stability of compounds containing both thioamides and thioureas. Our study questions the utility short-chain thioamide-based inhibitors of sirtuins for drug development and points to application of mono-alkylated thiourea-based chemotypes as more promising for targeting sirtuins 1 and 3, in particular.