EGF‐like and Other Disulfide‐rich Microdomains as Therapeutic Scaffolds

Disulfide bonds typically introduce conformational constraints into peptides and proteins, conferring improved biopharmaceutical properties and greater therapeutic potential. In our opinion, disulfide‐rich microdomains from proteins are potentially a rich and under‐explored source of drug leads. A survey of the UniProt protein database shows that these domains are widely distributed throughout the plant and animal kingdoms, with the EGF‐like domain being the most abundant of these domains. EGF‐like domains exhibit large diversity in their disulfide bond topologies and calcium binding modes, which we classify in detail here. We found that many EGF‐like domains are associated with disease phenotypes, and the interactions they mediate are potential therapeutic targets. Indeed, EGF‐based therapeutic leads have been identified, and we further propose that these domains can be optimized to expand their therapeutic potential using chemical design strategies. This Review highlights the potential of disulfide‐rich microdomains as future peptide therapeutics. Disulfide‐rich microdomains are underexplored scaffolds for therapeutic drug design. In this Review, the most abundant domains present in the animal and plant kingdoms are highlighted, and their structures and functional activities are analysed to provide an insight into their use in design of next‐generation peptide therapeutics.