Mono-N-terminal poly(ethylene glycol)–protein conjugates

A site-directed method of joining proteins to poly(ethylene glycol) is presented which allows for the preparation of essentially homogeneous PEG–protein derivatives with a single PEG chain conjugated to the amine terminus of the protein. This selectivity is achieved by conducting the reductive alkylation of proteins with PEG–aldehydes at lower pH. Working examples demonstrating the application of this method to improve the delivery characteristics and therapeutic value of several proteins are provided.