The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands

Abstract

Pentapeptides having the sequence R-HN-Ala-Val-X-Val-Leu-OMe, where the central residue X is L-serine, L-threonine, (2S,3R)-L-CF3-threonine and (2S,3S)-L-CF3-threonine were prepared. The capacity of (2S,3S)- and (2S,3R)-CF3-threonine analogues to stabilize an extended structure when introduced in the central position of pentapeptides is demonstrated by NMR conformational studies and molecular dynamics simulations. CF3-threonine containing pentapeptides are more prone to mimic β-strands than their natural Ser and Thr pentapeptide analogues. The proof of concept that these fluorinated β-strand mimics are able to disrupt protein–protein interactions involving β-sheet structures is provided. The CF3-threonine containing pentapeptides interact with the amyloid peptide Aβ1-42 in order to reduce the protein–protein interactions mediating its aggregation process.

Application of C-Terminal 7-Azabicyclo[2.2.1]heptane to Stabilize β-Strand-like Extended Conformation of a Neighboring α-Amino Acid

“…On the other hand, there are only a few examples of the latter approach, such as the use of stapling peptides (macrocyclization) 21 and interstrand or intramolecular hydrogen bond-stabilizing scaffolds such as 1,2-dihydro-3(6H)-pyridinone, 22 the unnatural amino acid Hao (5-hydrazino-2-methoxybenzoic acid), 23−25 aminopyrazole, 26 N-difluoromethyltriazole, 27 nine. 28 In these examples, formation of intra-and/or intermolecular hydrogen bonding stabilized paired β-sheet structures. Some important applications of these β-sheet peptide mimics include HIV-1 protease inhibitors and amyloid aggregation inhibitors.…”

“…There have been two strategies of molecular design to mimic β-strand structures and hydrogen-bonding β-sheet structures. One is the use of nonpeptidic scaffolds to attain shape similarities to β-strand-like extended structures, − and the other is utilizing amino acids and amino acid surrogates to stabilize interstrand hydrogen-bonding β-sheet structures, which includes macrocyclization (backbone or side chain to side chain) and replacement of amino acids. − A major difference between these two strategies is the absence or presence of the ability to form interstrand hydrogen bonding. Many examples of the former approach have been reported using various nonamino acid units such as dibenzofurans, , oligoureas, − metallopeptides, − indolin-3-ones, imidazolidin-2-ones, epiindolines, and oligothienylpyridines .…”

“…Therefore, their general applicability to mimic protein–protein interactions via β-sheet formation is unclear. On the other hand, there are only a few examples of the latter approach, such as the use of stapling peptides (macrocyclization) and interstrand or intramolecular hydrogen bond-stabilizing scaffolds such as 1,2-dihydro-3­(6 H )-pyridinone, the unnatural amino acid Hao (5-hydrazino-2-methoxybenzoic acid), − aminopyrazole, N -difluoromethyltriazole, and 4,4,4-trifluorothreonine . In these examples, formation of intra- and/or intermolecular hydrogen bonding stabilized paired β-sheet structures.…”