Discovery and Development of Covalent Activators: A Review

While covalent drugs have traditionally been developed as inhibitors, an emerging class of molecules that enhance protein function through covalent modification is attracting increasing attention. This review provides a comprehensive overview of the discovery, design, and development of this class of molecules, surveying key examples across diverse protein families, including nuclear receptors, G Protein-Coupled Receptors (GPCRs), enzymes, and ion channels. We highlight both serendipitously discovered and rationally designed covalent activators, offering insights into their distinct mechanisms of action and enabling their classification into mechanistic categories. We discuss the molecular mechanisms underlying covalent activation, the electrophilic warheads used to achieve target engagement, and the experimental evidence supporting their activity. Particular emphasis is placed on distinguishing examples with therapeutic potential from those that primarily serve as chemical biology tools. Where available, the medicinal chemistry routes of representative covalent activators are discussed, with attention to key considerations in electrophilic warhead installation. While some covalent activators have demonstrated promising pharmacological properties, the field remains at an early stage of development, and the discovery and optimization of these molecules differ fundamentally from those of covalent inhibitors. Accordingly, this review seeks to identify common mechanistic and medicinal chemistry principles that underpin diverse classes of covalent activators. Through comparative analysis across different protein families, we highlight how target biology, structural information, and protein dynamics influence activation strategies, electrophile selection, and activator design, providing a framework that may guide the rational development of future covalent activators. Finally, we discuss emerging opportunities, challenges, and future directions in the discovery and development of covalent activators.