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

• Published in: Chemistry : a European journal 2011-03, Vol.17 (14), p.3995-4004
• Main Authors: Knijnenburg, Annemiek D., Tuin, Adriaan W., Spalburg, Emile, de Neeling, Albert J., Mars-Groenendijk, Roos H., Noort, Daan, Otero, José M., Llamas-Saiz, Antonio L., van Raaij, Mark J., van der Marel, Gijs A., Overkleeft, Herman S., Overhand, Mark
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; amino acids; Amino Acids - chemistry; Amino Sugars; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; antimicrobial peptides; Circular Dichroism; conformation analysis; Gramicidin - chemistry; gramicidin S; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Molecular Structure; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; X-Ray Diffraction; β-turn
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201002895

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. Ring size matters: Monobenzylated sugar amino acids (SAAs) that differ in ether ring size (containing an oxetane, furanoid, and pyranoid ring, see scheme) are synthesized and incorporated in one of the β‐turn regions of the cyclo‐decapeptide gramicidin S (GS). The pyranoid SAA derivative is slightly less hydrophobic and interestingly it displays a diminished haemolytic activity, but has similar antimicrobial properties to GS.