Covalent Drugs – Advantages, Challenges, And Opportunities

By Simon Haydar, Senior VP and Head of Integrated Drug Discovery Solutions, Aragen Bioscience, Inc.

Covalent inhibitors are compounds designed to form a covalent bond with a specific molecular target. Covalent drugs (small molecule as well as protein/peptide) exhibit pharmacological advantages, such as prolonged duration of action and enhanced potency over non-covalent drugs, giving them a higher probability of efficacy in medicating hard-to-treat human diseases.

With unique mechanistic properties that differentiate them from non-covalent inhibitors, covalent drugs can be administered at a lesser dose and frequency, reducing off-target events and increasing patient compliance. Covalent drugs also can be effective for low-vulnerability targets, wherein high levels of occupancy are needed to generate the desired physiological outcome, as well as effective in drugging chemically intractable targets. Additionally, covalent therapeutics can be a strategy to overcome drug-resistance mutations in gene-encoding the target protein.

Current development of a variety of covalent inhibitors to address human health conditions, combined with recent FDA approval of several covalent therapeutics for use in humans, has energized interest in covalent therapeutics. Aragen offers clients of all sizes the required components to build a successful program from design to implementation, through measurement of efficacy and liability, all the way into data analysis, to generate a compound with as high a probability as possible of becoming a potential drug.