Paper Citing NAMD - Abstract
Li, Yangmei; Bionda, Nina; Yongye, Austin; Geer, Phaedra; Stawikowski, Maciej; Cudic, Predrag; Martinez, Karina; Houghten, Richard A.
Dissociation of Antimicrobial and Hemolytic Activities of Gramicidin S through N-Methylation Modification
CHEMMEDCHEM, 8:1865-1872, NOV 2013
beta-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 beta-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 beta-sheet antimicrobial peptide, gramicidinS (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 beta-strand and beta-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 beta-turn region. However, analogues containing N-methylleucine at beta-strand and N-methylalanine at beta-turn regions exhibited a fourfold increase in selectivity index compared to GS. We also examined the conformation of these N-methylated GS analogues using (HNMR)-H-1 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.
