Exploring the Conformational and Biological Versatility of β‐Turn‐Modified Gramicidin S by Using Sugar Amino Acid Homologues that Vary in Ring Size

Abstract

Monobenzylated sugar amino acids (SAAs) that differ in ether ring size (containing an oxetane, furanoid, and pyranoid ring) were synthesized and incorporated in one of the β-turn regions of the cyclo-decapeptide gramicidin S (GS). CD, NMR spectroscopy, modeling, and X-ray diffraction reveal that the ring size of the incorporated SAA moieties determines the spatial positioning of their cis-oriented carboxyl and aminomethyl substituents, thereby subtly influencing the amide linkages with the adjacent amino acids in the sequence. Unlike GS itself, the conformational behavior of the SAA-containing peptides is solvent dependent. The derivative containing the pyranoid SAA is slightly less hydrophobic and displays a diminished haemolytic activity, but has similar antimicrobial properties as GS.

Hairpin formation promoted by the heterochiral dinipecotic acid segment: A DFT study

“…GS adopted a C 2 ‐symmetric antiparallel β‐sheet with two type II′ β‐turns at the d ‐Phe‐Pro sequences . Several GS analogs, which contained thioindolizines, indolizines, sugar amino acids and their homologs, d ‐Pro‐Phe, morpholine amino acids, or di‐γ‐peptide at the d ‐Phe‐Pro sequence, have been studied with the aim of designing potent antimicrobial agents …”

“…The GS B ‐Nip 2 derivative favored solvation by 13.95 kcal mol −1 in CH 2 Cl 2 and by 24.97 kcal mol −1 in water at the SMD M06‐2X/6–31G(d) level of theory compared with those of GS B . It was expected that the replacement of the d ‐Phe‐Pro sequence of GS by the ( R )‐Nip‐( S )‐Nip segment might make GS less hydrophobic and decrease the hemolytic activity, as suggested for GS derivatives containing sugar amino acids as a turn motif . However, further experiments are needed to evaluate the antimicrobial activity of the GS B ‐Nip 2 derivative.…”

“…However, further experiments are needed to evaluate the antimicrobial activity of the GS B ‐Nip 2 derivative. Based on measurements of the CD spectra of GS and its derivatives containing sugar amino acids in methanol and water, it has been suggested that GS adopts the same secondary structure in both solvents; in contrast, its derivatives exhibited an enhanced excitation that differed between water and methanol, indicating that the secondary structure was more pronounced in methanol . To estimate the relative conformational flexibilities of GS and the GS B ‐Nip 2 derivative, we compared the conformational entropies of these compounds in CH 2 Cl 2 and in water.…”

Computationally designed β‐turn foldamers of γ‐peptides based on 2‐(aminomethyl)cyclohexanecarboxylic acid

“…GS adopts a C 2 ‐symmetric antiparallel β‐sheet with two type II′ β‐turns at the D ‐Phe‐Pro sequences 52–54. Several GS analogues, which contain thioindolizines, indolizines, sugar amino acids and their homologues, D ‐Pro‐Phe, or morpholine amino acids at the D ‐Phe‐Pro sequence, have been studied to design the potent antimicrobial agents 55–60. In the trigonal crystal of GS, there are one and a half crystallographically independent peptide molecules A and B (i.e., GS A and GS B ), of which the latter has the molecular C 2 symmetry axis 54…”

Approaches to Pyranuronic β‐Sugar Amino Acid Building Blocks of Peptidosaccharide Foldamers

“…Nowadays, SAAs are widely used in the design and synthesis of foldamers [2] as they have i) a versatile nature; ii) tunable properties in terms of ring size, stereochemistry, substituents, and conformation; iii) adjustable hydrophilic/hydrophobic character as a function of the free/protected nature of their OH groups. [3][4][5][6][7] A large number of cyclic SAAs based on αto ε-amino acid motifs have been described; these mainly have either furanoid or pyranoid rings. Homo-and heterooligomers built up from such building blocks using solid-phase peptide synthesis (SPPS) could form different secondary structural elements and designed backbone scaffolds, similar to those occurring in polypeptides and proteins, but with different dynamic properties.…”