Peptide-Based Targeted Covalent Inhibitors

Covalent inhibitors are one of many conventional covalent drugs and have garnered wide attention for their breakthrough advancements in overcoming drug resistance and improving selectivity. Among the component species for covalent inhibitors, peptide moieties have been broadly utilized to develop covalent inhibitors through serving as ligands to delivery vehicles, due to their advantages of large binding interfaces, reliable associating affinity, and excellent biocompatibility. Incorporating peptide ligands with electrophilic warheads with controllable reactivity leads to covalent inhibitors targeting specific proteins and mitigating off-target concern. However, inherent limitations such as poor membrane permeability and insufficient in vivo stability have constrained their clinical translation, necessitating the development of advanced delivery systems. Concurrently, self-assembly of peptides into nanostructures driven by noncovalent interactions gives rise to potential platforms to deliver covalent inhibitors and release them at targeting pathological sites, thus allowing for precise control of covalent inhibition. In this review, we systematically summarize recent progress in covalent inhibitors containing peptide ligands or delivered by peptide assemblies. Starting with the structure and activity mechanism of targeted covalent inhibitors, we introduce the design strategies for conventional peptide covalent inhibitors and their applications in disease-related targets. Following a brief discussion of the advance in controllable reactive electrophilic warheads, we highlight the delivery systems and the role of supramolecular assemblies in inducing proximity between noncovalent ligands and warheads. Eventually, we discuss the current challenges in clinical transformation and future development of covalent inhibitors, providing perspective for the development of the next generation of covalent drugs.