Abstract
Nature has long served as a prolific source of bioactive compounds, offering structurally diverse scaffolds for the development of therapeutics. In recent years, increasing attention has been given to nature-inspired covalent inhibitors, molecules that form covalent bonds with pathogen- or cancer-specific targets, due to their potential selectivity and sustained biological activity. This review explores the landscape of covalent inhibitors derived from natural sources, with a focus on compounds from fungi, marine organisms, bacteria and plants. In particular, emphasis is placed on the molecular mechanisms through which these compounds exert their activity against different types of pathogens and other biomedically relevant targets, highlighting key structural motifs that facilitate covalent interactions. Furthermore, the review discusses recent advances in synthetic modification, target identification, and optimization strategies that bridge natural compound discovery with modern drug development. By drawing insights from nature's chemical repertoire, this work ultimately displays the potential of natural covalent inhibitors as a promising foundation for next-generation anti-infective and anticancer therapeutics.