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The recently developed mRNA‐based coronavirus SARS‐CoV‐2 vaccines highlighted the great therapeutic potential of the mRNA technology. Although the lipid nanoparticles used for the delivery of the mRNA are very efficient, they showed, in some cases, the induction of side effects as well as the production of antibodies directed against particle components. Thus, the development of alternative delivery systems is of great interest in the pursuit of more effective mRNA treatments. In the present work, we evaluated the mRNA transfection capacities of a series of cationic histidine‐rich amphipathic peptides derived from LAH4. We found that while the LAH4‐A1 peptide was an efficient carrier for mRNA, its activity was highly serum sensitive. Interestingly, modification of this cell penetrating peptide at the N‐terminus with two tyrosines or with salicylic acid allowed to confer serum resistance to the carrier. [ABSTRACT FROM AUTHOR]

ABSTRACT Amphipathic peptides composed of alternating hydrophobic and hydrophilic amino acids are a privileged class of peptide, which have a high propensity to self-assemble into β-sheet fibrils. The Ac-(FKFE)2-NH2 peptide has been extensively studied and forms putative β-sheet bilayer fibrils in which the hydrophobic Phe side chains are organized to a single face of each constituent sheet; upon bilayer formation, these hydrophobic benzyl groups are sequestered in the hydrophobic core of the resulting fibril. In order for the Phe side chains to be uniformly displayed on one face of Ac-(FKFE)2-NH2 β-sheets, an antiparallel packing orientation in which one amino acid residue is unpaired must be adopted. Based on molecular models, we hypothesized that truncated seven amino acid derivatives of Ac-(FKFE)2-NH2 in which either the N-terminal Phe residue (Ac-KFEFKFE-NH2) or the C-terminal Glu residue (Ac-FKFEFKF-NH2) is eliminated should readily self-assemble into β-sheet bilayers in which all hydrogen bond and hydrophobic/charge interactions are satisfied. We found, however, that these minute changes in peptide sequence have unanticipated and dramatic effects on the self-assembly of each peptide. Ac-FKFEFKF-NH2 self-assembled into fibrils with unique morphology relative to the parent peptide, whereas the Ac-KFEFKFE-NH2 peptide had a strongly reduced propensity to self-assemble, even failing to self-assemble altogether under some conditions. These findings provide significant insight into the effect of sequence length and strand registry as well as hydrophobicity and charge on the self-assembly of simple amphipathic peptides to illuminate the possibility of tuning self-assembly processes and the resulting structures with minute changes to peptide sequence. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 100: 738-750, 2013. [ABSTRACT FROM AUTHOR]

Amphipathic peptides composed of alternating polar and nonpolar residues have a strong tendency to self-assemble into one-dimensional, amyloid-like fibril structures. Fibrils derived from peptides of general (XZXZ) n sequence in which X is hydrophobic and Z is hydrophilic adopt a putative β-sheet bilayer. The bilayer configuration allows burial of the hydrophobic X side chain groups in the core of the fibril and leaves the polar Z side chains exposed to solvent. This architectural arrangement provides fibrils that maintain high solubility in water and has facilitated the recent exploitation of self-assembled amphipathic peptide fibrils as functional biomaterials. This article is a critical review of the development and application of self-assembling amphipathic peptides with a focus on the fundamental insight these types of peptides provide into peptide self-assembly phenomena. © 2011 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 98: 169-184, 2012. [ABSTRACT FROM AUTHOR]

Two novel pore-forming peptides have been isolated from the venom of the South-African scorpion Opistophtalmus carinatus . These peptides, designated opistoporin 1 and 2, differ by only one amino acid and belong to a group of α-helical, cationic peptides. For the first time, a comparison of the primary structures of α-helical pore-forming peptides from scorpion venom was undertaken. This analysis revealed that peptides in the range of 40–50 amino acids contain a typical scorpion conserved sequence S(x)3 KxWxS(x)5 L. An extensive study of biological activity of synthesized opistoporin 1 and parabutoporin, a pore-forming peptide previously isolated from the venom of the South-African scorpion Parabuthus schlechteri , was undertaken to investigate an eventual cell-selective effect of the peptides. Opistoporin 1 and parabutoporin were most active in inhibiting growth of Gram-negative bacteria (1.3–25 µm), while melittin and mastoparan, two well-known cytolytic peptides, were more effective against Gram-positive bacteria in the same concentration range. In addition, the peptides showed synergistic activity with some antibiotics commonly used in therapy. Opistoporin 1 and parabutoporin had hemolytic activity intermediate between the least potent mastoparan and the highly lytic melittin. Furthermore, all peptides inhibited growth of fungi. Experiments with SYTOX green suggested that this effect is related to membrane permeabilization. [ABSTRACT FROM AUTHOR]

A class of peptides that associate with lipids, known as oblique-orientated peptides, was recently described [Brasseur R., Pillot, T., Lins, L., Vandekerckhove, J. & Rosseneu, M. (1997) Trends Biochem. Sci. 22, 167-171]. Due to an asymmetric distribution of hydrophobic residues along the axis of the α-helix, such peptides adopt an oblique orientation which can destabilise membranes or lipid cores. Variants of these oblique peptides, designed to have an homogeneous distribution of hydrophobic and hydrophilic residues along the helical axis, are classified as regular amphipathic peptides. These peptides are expected to lie parallel to the polar/apolar interface with their hydrophobic residues directed towards the apolar and their hydrophilic residues towards the polar phase. An hydrophobic, oblique-orientated peptide was identified at residues 56-68 in the sequence of the lecithin-cholesterol acyltransferase (LCAT), enzyme. This peptide is predicted to penetrate a lipid bilayer at an angle of 40+ through its more hydrophobic C-terminal end and thereby induce the destabilisation of a membrane or a lipid core. The LCAT-(56-68) wild-type peptide was synthesised together with the LCAT-(56-68, 0+) variant, in which the hydrophobicity gradient was abolished through residue permutations. In two other variants, designed to keep their oblique orientation, the W61 residue was shifted either towards the more hydrophilic N-terminal at residue 57, or to position 68 at the hydrophobic C-terminal end of the peptide. Peptide-induced vesicle fusion was demonstrated by fluorescence measurements using pyrene-labeled vesicles and by monitoring of vesicle size by gel filtration. The interaction between peptides and lipids was monitored by measurement of the intrinsic tryptophan fluorescence emission of the peptides. Fluorescence polarisation measurements, using diphenyl hexatriene, were carried out to follow changes in the lipid fluidity. The LCAT-(56-68) wild-type peptide and... [ABSTRACT FROM AUTHOR]