Psi[CH(CF(3))NH]Gly-peptides: synthesis and conformation analysis

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Structural Biology

Background:

• Peptides are crucial biomolecules, but their therapeutic applications are limited by poor stability and bioavailability.
• Peptidomimetics offer a promising alternative by mimicking peptide structures while enhancing stability.
• Developing novel peptide bond surrogates is essential for advancing peptidomimetic design.

Purpose of the Study:

• To synthesize and characterize a new class of peptidomimetics, Psi[CH(CF(3))NH]Gly peptides, utilizing a trifluoroethylamine group as a peptide bond surrogate.
• To investigate the conformational properties of these novel peptidomimetics, particularly their propensity for specific secondary structures.
• To explore the influence of stereochemistry on the folding behavior of these peptidomimetics.

Main Methods:

• Stereoselective synthesis involving the addition of alpha-amino acid esters to trans-3,3,3-trifluoro-1-nitropropene.
• Conformational analysis using Nuclear Overhauser Effect (NOE) spectroscopy, specifically ROESY experiments, to detect long-range interactions.
• Molecular dynamics (MD) calculations to predict and analyze the ensemble of possible conformations.

Main Results:

• Successful synthesis of Psi[CH(CF(3))NH]Gly peptides incorporating a trifluoroethylamine mimic.
• Evidence of both unfolded and folded conformations in model tetrapeptides, with folded structures stabilized by intramolecular hydrogen bonds.
• MD calculations revealed a preference for beta turn structures in L-peptides and a strong tendency towards beta hairpin formation in D-Pro containing peptides, driven by an additional hydrogen bond.

Conclusions:

• Psi[CH(CF(3))NH]Gly peptides represent a novel class of peptidomimetics with unique conformational characteristics.
• The trifluoroethylamine moiety can act as a stable peptide bond surrogate, influencing peptide folding.
• Stereochemistry, particularly at the Pro residue, plays a significant role in directing the formation of specific secondary structures like beta hairpins.