Synthesis of orthogonally protected non-natural amino acids
The development of bioinspired active ingredients is becoming increasingly important in nowadays pharmaceutical chemistry. One aspect of this is the incorporation of non-natural amino acids into peptides to counteract several problematic properties. Therefore, in our joint project, we will focus on two obstacles of peptides in which the non-natural amino acids we designed can provide a solution.
One of these areas is the poor water solubility and tendency for aggregation, which makes it difficult to formulate many pharmacologically active peptides. However, hydrophilicity can be increased by incorporating "super-hydrophilic" amino acids and aggregation can be disrupted with the use of disubstituted or beta amino acids.
Therefore, the basis of our research is the commercially non available α-hydroxymethyl serine and its side-extended, fluorine-containing and β-amino acid analogues which will be tested for their effects on known model peptides. (eg. Amyloidβ (30-37), Dau = Aoa-GFLG-GE11).
Another important problem is the formation and stabilization of cyclic peptides and turn structures, for which bulky amino acid derivatives containing nonafluoro-tert-butyl groups have been designed. Nonafluoro-tert-butyl groups can significantly influence the conformational properties of peptides, thus may contribute to the formation of diverse isomeric forms. Therefore, we intend to study the effect of these analogues on peptide configuration by incorporating them into model peptides, containing several disulfide bridges (e.g. α-conotoxin, protegrin-1).
Our work can create the core of a peptide-synthetic compound library that may provide solutions to multiple problematic areas in peptide chemistry and therefore, it can be the basis for other future collaborations.
Anikó Nemes, Nóra Kata Enyedi