Preferred Conformations of Peptides Containing tert‐Leucine, a Sterically Demanding, Lipophilic α‐Amino Acid with a Quaternary Side‐Chain C^β Atom

Abstract

Terminally protected homopeptides of tert-leucine, from the dimer to the hexamer, co-oligopeptides of tert-leucine in combination with alpha-aminoisobutyric acid or glycine residues up to the hexamer level, and simple dipeptides representing known scaffolds for catalysts in asymmetric organic reactions were prepared by solution methods and fully characterized. The results of conformation analysis, performed by use of FT-IR absorption, NMR, CD, and X-ray diffraction techniques, indicate that this hydrophobic alpha-amino acid with tetrasubstitution at the Cbeta atom is structurally versatile. We show that it prefers extended or semiextended conformations, but can also be accommodated in folded structures, provided that these are biased by the presence of helicogenic residues. The current large-scale production of Tle, combined with its conformational preferences unravelled in this work, should make this bulky, hydrophobic, Calpha-trisubstituted alpha-amino acid a regular building block of any strategy seeking to tailor peptides with improved catalytic and pharmacological properties.

Novel Furin Inhibitors with Potent Anti‐infectious Activity

“…[51] Comparison of the new crystal structure of inhibitor 19 with the previously solved furin structures in complex with P3 Vala nalogues [21] revealed that the terminal methyl groups of Valc an be perfectly superimposed with two sidechain methyl groups found in the Tle structure. For the additional third methyl group in Tle, we could not identify any specific contact with furin that could easily explain the improved affinity.I ti s, however,i nvolved in additional close intramolecular van der Waals contacts to the amide hydrogen atom (with ad istance to the nitrogen of 3.1 ) and to the carbonyl oxygen atom (3.5 ) of the P2 Arg residue.…”

Effect of the powerful plasticity of the tert‐butyl side chain on the conformational equilibrium of ascidiacyclamides

“…In structure-supporting solvents, Tle homopeptides are much less folded than their Leu, Val, or Ile counterparts, and they tend to extensively self-associate. 13 Structural analyses of a combination peptide composed of α-aminoisobutyric acid (Aib) and Tle have also been performed. 13 Aib is strongly helicogenic due to its gemdimethylation at the α-carbon, 14,15 and Aib homopeptides adopt a 3 10 -helical structure.…”

Novel α-MSH Peptide Analogues with Broad Spectrum Antimicrobial Activity

“…The amphipathic helical structure along residues 8–13 is likely responsible for the superior antimicrobial activity of the substituted peptides whereas the partial lack of helicity in DNal probably contributes to its reduced activity. Indeed, the residues Deg [26], tButGly [27], Ac3c [36], β-Ala [31], and Acpc [32], which do not stabilize regular right handed helices, did not promote activity in the corresponding peptides.Therefore, consistent with previous observations, the amphipathic helical content proved to be a key factor in the activity of antimicrobial peptides [37], [38].…”

“…Conversely, diethylglycine (Deg) containing peptides have a greater tendency to form extended backbone conformations in strongly interacting solvents such as water [26]. Similarly, the tert -butyl glycine (tButGly) also called tert -leucine residue, inserted in peptide 3 , prefers extended (β sheet-like) or semiextended [(Pro) n -like] conformations [27]. Peptides 1 and 2 containing an Aib and a Deg residue in position 10, respectively, did not show antimicrobial activity.…”