Cell selectivity and interaction with model membranes of Val/Arg‐rich peptides

Abstract

Antimicrobial peptides are major components of the innate self-defence system and a large number of peptides have been designed to study the mechanism of action. In the present study, a small combinatorial library was designed to study whether the biological activity of Val/Arg-rich peptides is associated with targeted cell membranes. The peptides were produced by segregating hydrophilic residues on the polar side and hydrophobic residues on the opposite side. The peptides displayed strong antimicrobial activity against Gram-negative and Gram-positive bacteria, but weak haemolysis even at a concentration of 256 µM. CD spectra showed that the peptides formed α-helical-rich structure in the presence of negatively charged membranes. The tryptophan fluorescence and quenching experiments indicated that the peptides bound preferentially to negatively charged phospholipids over zwitterionic phospholipids, which corresponds well with the biological activity data. In the in vivo experiment, the peptide G6 decreased the bacterial counts in the mouse peritoneum and increased survival after 7 days. Overall, a high binding affinity with negatively charged phospholipids correlated closely with the cell selectivity of the peptides and some peptides in this study may be likely candidates for the development of antibacterial agents.

Overexpression of atypical protein kinase C in HeLa cells facilitates macropinocytosis via Src activation

“…It is possible that the peptidomimetic binds directly to anionic lipids in cell membranes via the basic residues, as do many cell penetrating peptides that are rich in arginine and lysine [42, 60–62]. In that case, aPKC-PS peptide could serve as a platform to associate with and maintain the kinase in the unfolded active conformation on cellular membranes, and thereby exposing the SH3 binding domain in aPKC for interaction with Src.…”

Strategies employed in the design and optimization of synthetic antimicrobial peptide amphiphiles with enhanced therapeutic potentials

“…To date, numerous studies have convincingly established that strong antimicrobial potencies (MIC b10 μM) can be achieved with engineered synthetic AMPs consisting exclusively of one cationic amino acid with another non-polar amino acid [34][35][36][37][38][39][40][41][42]. In the de novo design of AMPs, Arg and Lys are popular choices among the basic amino acids as they are protonated under physiological conditions and have been found to confer strong antimicrobial activities.…”

Strand Length-Dependent Antimicrobial Activity and Membrane-Active Mechanism of Arginine- and Valine-Rich β-Hairpin-Like Antimicrobial Peptides

“…We have recently designed a series of ␣-helical peptides that are rich in valine (V) and arginine (R) residues and have potent antimicrobial activity (23). The effect of the VR or RV motif on the biological activities of ␤-hairpin-like antimicrobial peptides has not been studied.…”