Inhibitors containing unusual amino acids refer to the collection of all inhibitors containing unnatural amino acids in the molecular structure, such as peptide inhibitors, protease inhibitors, kinase inhibitors and so on.
The number of functional groups carried by 20 natural amino acids is limited, which can not meet the needs of protein structure and function in chemical and biological research and application. Unnatural amino acids artificially endowed with diverse functional groups are outstanding in protein modification. These unusual amino acids contain diverse functional groups such as ketone, aldehyde, azide, alkynyl, alkenyl, amide, nitro, phosphate and sulfonate, which can carry out a variety of modification reactions, such as click chemistry, photochemistry, glycosylation, fluorescence color development and so on. The modification of proteins by inhibitors containing unusual amino acids has brought new opportunities for the theoretical research and application of their structure and function.
Inhibitors containing unusual amino acids can be synthesized by the combination of solid-phase peptide synthesis and semi synthesis. However, the application of this technology is limited by the chemical properties of the required protective groups, connecting sites, protein folding and so on.
Biosynthesis in vitro can couple tRNA from connected natural amino acids and combine tRNA with unusual amino acids. Then, the cell translation system uses these aminoacylated tRNAs with unusual amino acids to synthesize inhibitors containing unusual amino acids under the corresponding blank codon or coding codon.
In vivo, site-specific modification of proteins by microinjection technology comes from the expansion of biosynthesis methods in vitro. However, it inherits the shortcomings of the biosynthesis method in vitro, that is, the aminoacylated tRNA cannot be reused and can only be applied to the cell mouth that can be microinjected.
Post-translational modification of protein plays a very important role in life. It makes the structure of inhibitors containing unusual amino acids more complex, the regulation more fine and the function more specific. The common post-translational modification processes include ubiquitination, phosphorylation, glycosylation, liposylation, methylation and acetylation.
Inhibitors containing unusual amino acids, such as enzyme inhibitors, could play an efficient role in organic solvents after chemical modification. Meanwhile, at the same temperature, the hydrogen bond in natural protein molecules will break, resulting in structural changes and protein denaturation. Inhibitors containing unnatural amino acids enhance thermal stability.
Inhibitors containing unusual amino acids has selectivity to related transporters and can block the uptake of neutral amino acids in mouse small intestine turnover model, so it can be used to treat diabetes. Inhibitors containing unusual amino acids can specifically target mitochondria, interact with mitochondrial outer membrane protein, cause mitochondrial dysfunction, and then cause mitochondrial autophagy to play an anti-tumor role.
The combination of inhibitors containing unusual amino acids and related atoms can be used to clarify the conformational changes of related proteins at ligand sites, and can also explain the complex dynamic phenomena of mammalian related proteins.