Chemical protein modification has become a valuable tool for developing modified proteins. The complementary use of genetic and chemical approaches provides a large toolbox that allows the preparation of almost unlimited protein constructs from natural or synthetically modified residues. This protein chemical diversity is usually achieved after translation, often referred to as post-translational protein modification (PTM), and is often responsible for much of the biodiversity found in nature. These modifications include acylation, methylation, phosphorylation, sulfation, faranzylation, ubiquitination, and glycosylation, and play key roles in important cellular processes, including transport, differentiation, migration, and signaling. Therefore, replicating this natural modification of a protein in an efficient and controlled manner (by introducing natural PTM) will provide an invaluable tool for studying its precise function. In addition, the possibilities offered by introducing and (biological) orthogonal modifications of non-natural parts/amino acids (which usually improve the properties of natural PTM during isolation, analysis and processing) make site-selective modification of proteins a key tool for interrogation and intervention in in vitro and in vivo biological systems.
Given the range of chemical modification methods available, it is now possible to decide which residues to target and which modifications to link to confer desired properties/functions (affinity probes, fluorophores, reaction tags, etc.). For example, increasing the circulating half-life of therapeutic proteins can be achieved by adding polyethylene glycol (PEG). On the other hand, the use of spectral markers to monitor the distribution of biomolecules in vivo enables the construction of highly selective imaging agents. Despite great advances in the field of bioconjugated chemistry, scientists still face many challenges, not only in terms of synthesis, but also in terms of processing, manufacturing, safety, and stability. Many methods have been developed and applied to the modification of specific proteins and may therefore not be applicable to any protein of interest. Therefore, there is still a need to develop mild, effective and robust complementary reactions for selective chemical modification of protein sites. Some comments covering different aspects of protein chemical synthesis, natural chemical connection from the more general strategies and endogenous amino acid modified to more specialized topics, such as clicking the modification agreement, the introduction of specific PTM, including glycosylation, polyethylene glycol (peg), (5 b, 10) in the past decade, the initiator of polymerization and polymerization based on protein, And challenging labeling of specific proteins of interest in complex cell mixtures using so-called “biological orthonormal” reactions.
Although subsequent publication describes in detail the different protein synthesis/modification, but the purpose of this review is not for all of the available biological coupling method carries on the detailed investigation, but about the recent chemical strategies for site selective modification of protein, such as rapid sulfur exchange or stable formation, no light and metal sulfide cycloaddition, And other metal-mediated protocols that are particularly challenging. This review will be divided into two parts: transition metal-free and transition metal-mediated approaches. For clarity, we will be in the whole manuscript with the following terms: residue/amino acid/site selectivity (or site selective) reaction is the priority to modify an amino acid residues rather than other amino acid residues (for example, cysteine and lysine) and, therefore, can be considered to be chemical reaction selectivity of example; On the other hand, the transformation described as regionally selective preferentially modifies only one of the same set of amino acids, especially when more than one is present in the same molecule (e.g., lysine exposed to a solvent versus internal lysine).