1571105-47-9Relevant articles and documents
Dissociation of antimicrobial and hemolytic activities of gramicidin S through N-methylation modification
Li, Yangmei,Bionda, Nina,Yongye, Austin,Geer, Phaedra,Stawikowski, Maciej,Cudic, Predrag,Martinez, Karina,Houghten, Richard A.
, p. 1865 - 1872 (2014/01/06)
β-Sheet antimicrobial peptides (AMPs) are well recognized as promising candidates for the treatment of multidrug-resistant bacterial infections. To dissociate antimicrobial activity and hemolytic effect of b-sheet AMPs we hypothesize that N-methylation of the intramolecular hydrogen bond(s)-forming amides could improve their specificities for microbial cells over human erythrocytes. We utilized a model b-sheet antimicrobial peptide gramicidin S (GS) to study the N-methylation effects on the antimicrobial and hemolytic activities. We synthesized twelve N-methylated GS analogues by replacement of residues at the β-strand and β-turn regions with N-methyl amino acids and tested their antimicrobial and hemolytic activities. Our experiments showed that the HC50 values increased fivefold compared with that of GS when the internal hydrogen-bonded leucine residue was methylated. Neither hemolytic effect nor antimicrobial activity changed when proline alone was replaced with N-methylalanine in the b-turn region. However analogues containing N-methylleucine at β-strand and N-methylalanine at β-turn regions exhibited a fourfold increase in selectivity index compared to GS. We also examined the conformation of these N-methylated GS analogues using 1H NMR and circular dichroism (CD) spectroscopy in aqueous solution and visualized the backbone structures and residue orientations using molecular dynamics simulations. The results show that N-methylation of the internal hydrogen bond-forming amide affected the conformation backbone shape and side chain orientation of GS.