Covalent peptides and proteins for therapeutics

Drugs with a covalent mechanism of action benefit from enhanced potency, selectivity, and in vivo efficacy. Historically, the only covalent drugs on the market have been covalent small molecules. However, many proteins and protein-protein interactions cannot be targeted by small molecules due to their lack of small molecule binding pockets, and are thus deemed undruggable. In order to drug the undruggable, peptide and protein therapeutics that can better bind to flat protein surfaces have been developed. Until recently, peptide and protein therapeutics have had noncovalent mechanisms of action. The recent advancement of unnatural amino acid chemistry, along with the development of better and more specific electrophilic warheads, has allowed for the application of covalent mechanisms to peptide and protein drugs. Covalent peptide and protein therapeutics have the potential to benefit from the same advantages that covalent small molecules have over their noncovalent counterparts. Here we provide a brief overview of the chemistry that makes this advancement possible, as well as examples of covalent peptides and the first covalent protein drug. These examples successfully crosslink their target proteins and have beneficial therapeutic effects.

Automated summary

Drugs with a covalent mechanism of action have advantages in potency, selectivity, and in vivo efficacy. While traditionally limited to small molecules, recent advancements in peptide and protein therapeutics have allowed for the targeting of previously undruggable proteins and protein-protein interactions using covalent mechanisms.