Structural and Dynamic Insights into a Glycine-Mediated Short Analogue of a Designed Peptide in Lipopolysaccharide Micelles: Correlation Between Compact Structure and Anti-Endotoxin Activity

In this study, we report an interaction study of a 13-residue analogue peptide VG13P (VARGWGRKCPLFG), derived from a designed VG16KRKP peptide (VARGWKRKCPLFGKGG), with a Lys6Gly mutation and removal of the last three residues Lys14-Gly15-Gly16, in lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria and responsible for sepsis or septic shock. VG13P displays an enhanced anti-endotoxin property as evident from significant reduction in LPS-induced TNF-α gene expression levels in a monocytic cell line, while it retains almost unchanged antimicrobial activity as its parent VG16KRKP against Gram-negative bacterial as well as fungal pathogens. In addition, in vitro LPS binding properties of VG13P in comparison to its parent VG16KRKP also remained unhindered, suggesting that the flexible C-terminal end of VG16KRKP may not play a major role in its observed antibacterial and LPS binding properties. An NMR-resolved solution structure of VG13P in LPS reveals two consecutive β-tu...