Selective N-terminal modification of peptides and proteins using acyl phosphates

Selective acylation of the N-terminus over side-chains in peptides and proteins is a highly desirable but challenging reaction in chemical biology. Here we report a biomimetic approach using enzymatic in situ activation of carboxylic acids with ATP to generate reactive acyl-adenosine phosphates, which display high selectivity for the N-termini of peptides and proteins, including pharmaceutically relevant liraglutide, insulin and glucagon. The acylation tolerates a range of unsubstituted and substituted fatty acids including di-acids, thus making it suitable for N-terminal biorthogonal labelling strategies.