About the Special Issue

Targeted covalent inhibitors are steadily gaining popularity in recent years, with almost 9,000 publications reported in the last decade. Combining a reactive 'warhead' suitably attached to a molecular skeleton that guides the selective binding to the target confers unique features to the mechanism of action of covalent drugs. The advantages of this therapeutic strategy include the use of lower therapeutic dosages concomitant to the enhanced pharmacology potency of the covalent bond, an extended therapeutic action that is determined by the target turnover rate of the target protein, and a reduced liability for drug-drug interaction due to the combined effect arising from low dosage and high selectivity. However, the therapeutic efficiency faces serious challenges, as the formation of a covalent adduct is conditioned to a high selectivity to avoid binding to unintended proteins, which otherwise could result in off-target effects, and the risk to promote structural changes that confer resistance, preventing the covalent inhibitor from effectively binding to the target, reducing the long-term efficacy.

A tuned design that leverages the intrinsic reactivity of the warhead, the chemical stability of the covalent bond, and the specificity for the binding site is needed for the success of targeted covalent inhibitors. On the other hand,this has to be supplemented witha tailored biochemical and biophysical toolkit addressing the experimental characterization in covalent-specific assays, emphasizing key aspects related to kinetic reactivity, residence time, exposure, and target occupancy. Furthermore, novel applications can be envisaged beyond the clinical therapeutics, covering the design of chemical probes or even the implementation in targeted protein degradation.

Overall, covalent inhibitors have great potential to open new horizons in drug therapeutics, enriching the toolbox of medicinal chemistry, enhancing the scenario of covalently-targeted diseases and, last but not least, increasing the options to mine novel avenues for intellectual property in clinical development.

This special issue aims to gather high quality research or review papers on the design, synthesis and pharmacological application of covalent inhibitors, including both in silico and experimental studies addressing the strategy to select appropriate warheads and their attachment to the chemical scaffold of the bioactive compound, the modulation of the chemical reactivity and target selectivity, the mechanism of covalent modification and the optimization of the pharmacological profile, with the ultimate goal of enhancing the medicinal chemistry toolbox in drug discovery of covalent inhibitors.

Keywords: Covalent inhibitors; reactive warhead; target selectivity; drug discovery

Call for Papers