The Application Of Non-Natural Amino Acids In The Synthesis Of Constrained Peptides

Peptide drugs are a new class of drug molecules with molecular weight between small molecular drugs and protein drugs. This class of drug molecules possesses higher activity and selectivity compared with small molecule drugs and is able to act on the protein-protein interaction interface; compared with protein drugs, peptide drugs can act on intracellular targets after transformation. Therefore, it has broad application prospects. However, the polypeptide molecules generally have the disadvantage of poor protease stability and poor cell membrane permeability, and the impalpable structure of the polypeptide can cause a decrease or even loss of its activity. In this paper, the authors introduce a non natural amino acid unit in the polypeptide to improve the above properties.The following two aspects of the work are mainly included:1. The application of a-methyl diaminodiacids to solid-phase synthesis of all-hydrocarbon constrained a-helical stapled peptideProtein-protein interactions mediate a number of important biological processes, including the processes associated with human diseases, and thus have become a new generation of therapeutic targets. Proteins often interact with each other via secondary structure, and a-helix is the most common protein secondary structure, often appear in many important protein-protein interactions. Therefore, the use of this folding module to regulate protein-protein interaction is very potential. In this paper, we synthesized a series of all-hydrocarbon bridged a-methyl diaminodiacids and introduced them into peptides by solid-phase synthesis, and obtained all-hydrocarbon constrained a-helical stapled peptide. We found that compared to natural polypeptide, the all-hydrocarbon constrained a-helical stapled peptide have a more stable secondary structure and higher protease stability; at the same time, we also used the a-helical stapled peptide to regulate the cancer related Wnt/β-Catenin signaling pathway, and found that its inhibition activity of Wnt signaling pathway was also improved.2. New method to the synthesis of dicarba cystine surrogatesA lot of cyclic peptide drug molecules usually contain one or more disulfide bonds, however, disulfide bonds are sensitive to reducing condition; and when multiple disulfide bonds exist, isomerization will occur under the action of disulfide bond isomerase, leading to loss of their activity. To this end, bioisosteric and metabolically stable surrogates were used to replace the disulfide bond in cyclic peptide molecule. In this paper, the authors developed a new method for the efficient synthesis of dicarba cystine surrogates. In this method, the cross coupling of differently protected L-homoserine bromides generated orthogonally protected dicarba cystine surrogates. The dicarba cystine surrogates can be introduced into peptide molecules by solid-phase synthesis and obtain dicarba analogues of peptide with disulfide bond replacement by carbon-carbon bond.