Alkynyl Amino Acids

Background of Alkynyl Amino Acids

Alkynyl groups are very important functional groups. Click chemistry based on the reaction of terminal alkynyl groups with azides plays an important role in research areas such as drug screening, chemical biology and proteomics.

Alkynyl amino acids are unnatural amino acids which are capable of cyclisation reactions with azides to produce highly stable triazole linkers. This reaction enables the synthesis of cyclic peptides or stapled peptides, or the linking of peptides to dyes, radioactive tracers, antibodies or complex biomolecules to prepare bioconjugates and increase their biocompatibility in the absence of catalysts. Alkynyl amino acids have important applications in solid-phase peptide synthesis or liquid-phase synthesis.

Biosynthesis of Alkynyl Amino Acids

Alkynyl amino acids are found in both bacteria and fungi and can be located either at the end of the side chain or inside the side chain. In amino acids, halogenases catalyse the halogenation reaction to link a halogen atom to the side chain of the amino acid, then oxidases break the side chain to form the terminal double bond, and finally cleavage enzymes remove the halogen atom from the side chain of the amino acid to form the terminal alkyne group.

Applications of Alkynyl Amino Acids

(1) For Bio-orthogonal Assays

The introduction of bio-orthologous functional groups through the insertion of non-natural amino acids of different structures allows the introduction of different modifications to proteins, enabling the study of their properties and functions. An example is the introduction of S-propynyl cysteine at the protein interface, which can either form bonds or break them under mild conditions. In addition, it can link modifications by click reactions and can also link proteins by sulfhydryl-alkynyl reactions. Furthermore, due to its small size, it can be inserted into the enzymatic active site within the protein and thus modulate the enzyme activity. It is virtually non-cytotoxic and highly stable, making it an efficient tool for bio-orthogonal assays.

(2) For Peptide Synthesis

Short-chain peptides with a helical structure often have difficulty in maintaining their secondary structure in solution and are therefore unable to achieve high binding constants and membrane permeability, which prevents them from exerting their pharmaceutical activity. Alkynyl amino acids can be used for the synthesis of stapled peptides. This is usually achieved by cross-linking or bridging amino acids containing azides or electron-less nitrile with amino acids containing alkynyl (e.g. lysine, glutamic acid or aspartic acid) to create a more stable structure, which facilitates increased membrane permeability to therapeutic targets. This synthetic technique has important applications in the optimisation of drug delivery systems.

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