Abstract
Unnatural amino acids have tremendously expanded the folding possibilities of peptides and peptide mimics. While α,α-disubstituted and β-amino acids are widely studied, γ-derivatives have been less exploited. Here we report the conformational study on the bicyclic unnatural γ amino acid, 4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole-3-carboxylic acid 1. In model peptides, the (+)-(3aR6aS)-enantiomer is able to stabilize α-turn conformation when associated to glycine, as showed by 1H-NMR, FT-IR, and circular dichroism experiments, and molecular modeling studies. α-turn is a structural motif occurring in many biologically active protein sites, although its stabilization on isolated peptides is quite uncommon. Our results make the unnatural γ-amino acid 1 of particular interest for the development of bioactive peptidomimetics.
Highlights
Amino acids are the key building blocks of proteins and biomolecules and are widely exploited in different applications, from pharmaceutical chemistry and biomedicine to material science, optoelectronics and catalysis (Zhang et al, 2012; Mikhalevich et al, 2017; Solomon et al, 2017; López-Andarias et al, 2018; Raymond and Nilsson, 2018)
We investigated the conformational behavior of both the enantiomers of the bicyclic unnatural γ amino acid 4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole-3-carboxylic acid 1, obtained starting from the corresponding ethyl esters recently described by us (Tamborini et al, 2015)
Starting from the (–)-(3aS6aR)-1 and (+)-(3aR6aS)-1 enantiomers, model peptides containing Leu-Val dipeptide at C-terminus and variable sequences at N-terminus were prepared. Their conformational behavior was investigated by NMR spectroscopy, FT-IR, circular dichroism, and molecular modeling
Summary
Amino acids are the key building blocks of proteins and biomolecules and are widely exploited in different applications, from pharmaceutical chemistry and biomedicine to material science, optoelectronics and catalysis (Zhang et al, 2012; Mikhalevich et al, 2017; Solomon et al, 2017; López-Andarias et al, 2018; Raymond and Nilsson, 2018). Starting from the (–)-(3aS6aR)-1 and (+)-(3aR6aS)-1 enantiomers, model peptides containing Leu-Val dipeptide at C-terminus and variable sequences at N-terminus were prepared Their conformational behavior was investigated by NMR spectroscopy, FT-IR, circular dichroism, and molecular modeling. Our results indicated that (+)-(3aR6aS)-1 enantiomer, in combination with glycine, is effective in stabilizing the α-turn conformation in peptides (Figure 1) This structural motif occurs quite often in many key sites of proteins, such as enzyme active site, and metal binding domains (Wintjens et al, 1996), few molecules are known to mimic or stabilize it on isolated peptides (Kelso et al, 2004; Hoang et al, 2011; Krishna et al, 2014; Wang et al, 2018.).
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