Synthesis of Unnatural α,α-Methylated Tyrosine and Phenylalanine Amino Acids for Peptide Therapeutics
Disciplines
Medicinal-Pharmaceutical Chemistry | Organic Chemistry | Therapeutics
Abstract (300 words maximum)
Peptide-based therapeutics have attracted a lot of attention in recent years due to their great selectivity and lower side effects compared to small-molecule medicines. To avoid destruction due to the severe acidic conditions in the stomach and the presence of proteases in the small intestine, peptide medications must be injected into patients. Unnatural-amino acids such as α,α-disubstituted amino acids have two carbon substituents on the α-carbon, which bears the amino and carboxylic acid groups. They have been applied in a range of applications, such as physiologically active peptide conformational modifiers and pharmaceutical chemistry as building blocks to produce biologically active molecules. Herein, we have successfully synthesized precursors for α,α-methylated tyrosine and phenylalanine, which can be used in peptide treatments. The α,α-methyl groups on the amino acid scaffold cause steric hindrance to the peptide backbone, promoting strong intermolecular π-π stacking interactions between the two aromatic phenyl rings on the same side of the peptide. This results in a noncovalently stapled helical peptide. This non-covalent interaction generates unnatural-amino acids that proteases are unable to recognize, resulting in unusually stable peptides in serum.
Academic department under which the project should be listed
CSM - Chemistry and Biochemistry
Primary Investigator (PI) Name
Carl Saint-Louis
Synthesis of Unnatural α,α-Methylated Tyrosine and Phenylalanine Amino Acids for Peptide Therapeutics
Peptide-based therapeutics have attracted a lot of attention in recent years due to their great selectivity and lower side effects compared to small-molecule medicines. To avoid destruction due to the severe acidic conditions in the stomach and the presence of proteases in the small intestine, peptide medications must be injected into patients. Unnatural-amino acids such as α,α-disubstituted amino acids have two carbon substituents on the α-carbon, which bears the amino and carboxylic acid groups. They have been applied in a range of applications, such as physiologically active peptide conformational modifiers and pharmaceutical chemistry as building blocks to produce biologically active molecules. Herein, we have successfully synthesized precursors for α,α-methylated tyrosine and phenylalanine, which can be used in peptide treatments. The α,α-methyl groups on the amino acid scaffold cause steric hindrance to the peptide backbone, promoting strong intermolecular π-π stacking interactions between the two aromatic phenyl rings on the same side of the peptide. This results in a noncovalently stapled helical peptide. This non-covalent interaction generates unnatural-amino acids that proteases are unable to recognize, resulting in unusually stable peptides in serum.