Stereocontrolled protein surface recognition using chiral oligoamide proteomimetic foldamers

Abstract

An oligoamide helix mimicking foldamer with well-defined conformation is shown to recognize its target protein hDM2 in a manner that depends upon the composition, spatial projection and stereochemistry of functional groups appended to the scaffold.

An α‐Helix‐Mimicking 12,13‐Helix: Designed α/β/γ‐Foldamers as Selective Inhibitors of Protein–Protein Interactions

“…Thep roteolytic stability of a/b/g-peptides 1-8 was investigated using a-chymotrypsin (a-CT) as ar epresentative protease,s ince this enzyme selectively hydrolyses the amide bond on the C-terminal side of hydrophobic residues such as Leu, Tr p, and Phe,a ll of which are present in the a/b/gpeptide sequences.T he p53 [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] peptide was also studied for comparison (see the Supporting Information). Using HPLC to assess the progress of peptide digestion, it transpired that all eight a/b/g-peptides displayed considerably greater resistance to a-CT than did the native p53 [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] (!…”

“…Using HPLC to assess the progress of peptide digestion, it transpired that all eight a/b/g-peptides displayed considerably greater resistance to a-CT than did the native p53 [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] (! 32-fold for 2, 4, 6, and 8 and !…”

“…Peptides 1-8 were subjected to ab initio geometry optimization by DFT using Gaussian09 at the B3LYP/6-311G(d,p) level of theory. Thel owest-energy structures of 1-4 and 5-8 were superimposed (Figure 3a,b) and the backbone of peptide 2 (as ar epresentative example) was overlaid with the crystal structure of p53 [16][17][18][19][20][21][22][23][24][25][26][27][28][29] (Figure 3c)u sing g 4 -amino acid C(a) atoms as the basis of the alignment. Thesuperimposition gave an excellent RMSD value of around 0.9 (Figure 3d,e), thus strongly suggesting that the a/b/g-peptides 1-8 effectively mimic an a-helix.…”

“…[15,16] Ap articularly fertile area is centred on the search for foldamers that mimic natural secondary structures (specifically a-helices) and thereby act as inhibitors of protein-protein interactions (PPIs). [17][18][19][20][21] However,t here is still aneed to develop ligands that more effectively mimic the conformation and molecular recognition capabilities of the ahelix. Herein, we present the bottom-up design of hybrid a/b/ g-peptides that assume an a-helix-mimicking 12,13-helical conformation and function as effective inhibitors of the p53/ hDM2 interaction.…”

“…[40] Twos eries of four a/b/g-hexapeptides (1-8; Figure 1) were proposed: N-Boc-protected (1-4)a nd N-acetamide (5-8)p eptides.B oth series featured g 4 -Leu and Leu at the Cterminus,s ince only the amino acid side chain was aprerequisite,aswell as g 4 -Trp and g 4 -Phe,since previous studies have shown that the replacement of indole with phenyl in the Tr p21-mimicking position does not necessarily alter the affinity of peptidomimetics for hDM2. [18] Peptides 1-8 were prepared by using standard solution-state methods (see the Supporting Information), and conformational analysis was performed by using solution-state spectroscopic techniques and molecular modelling.…”