ABSTRACT
Ribosomally expressed proteins perform multiple, versatile, and specialized tasks throughout Nature. In modern times, chemically modified proteins, including improved hormones, enzymes, and antibody-drug-conjugates have become available and have found advanced industrial and pharmaceutical applications. Chemical modification of proteins is used to introduce new functionalities, improve stability or drugability. Undertaking chemical reactions with proteins without compromising their native function is still a core challenge as proteins are large conformation dependent multifunctional molecules. Methods for functionalization ideally should be chemo-selective, site-selective, and undertaken under biocompatible conditions in aqueous buffer to prevent denaturation of the protein. Here the present challenges in the field are discussed and methods for modification of the 20 encoded amino acids as well as the N-/C-termini and protein backbone are presented. For each amino acid, common and traditional modification methods are presented first, followed by more recent ones.
Subject(s)
Amino Acids , Proteins , Proteins/chemistryABSTRACT
Sulphur-selective conjugate addition reactions play a central role in synthetic chemistry and chemical biology. A general tool for conjugate addition reactions should provide high selectivity in the presence of competing nucleophilic functional groups, namely nitrogen nucleophiles. We report CO2-mediated chemoselective S-Michael addition reactions where CO2 can reversibly control the reaction pHs, thus providing practical reaction conditions. The increased chemoselectivity for sulphur-alkylation products was ascribed to CO2 as a temporary and traceless protecting group for nitrogen nucleophiles, while CO2 efficiently provide higher conversion and selectivity sulphur nucleophiles on peptides and human serum albumin (HSA) with various electrophiles. This method offers simple reaction conditions for cysteine modification reactions when high chemoselectivity is required.
