Antiviral Lipopeptide-Cell Membrane Interaction Is Influenced by PEG Linker Length

Abstract

A set of lipopeptides was recently reported for their broad-spectrum antiviral activity against viruses belonging to the Paramyxoviridae family, including human parainfluenza virus type 3 and Nipah virus. Among them, the peptide with a 24-unit PEG linker connecting it to a cholesterol moiety (VG-PEG24-Chol) was found to be the best membrane fusion inhibitory peptide. Here, we evaluated the interaction of the same set of peptides with biomembrane model systems and isolated human peripheral blood mononuclear cells (PBMC). VG-PEG24-Chol showed the highest insertion rate and it was among the peptides that induced a larger change on the surface pressure of cholesterol rich membranes. This peptide also displayed a high affinity towards PBMC membranes. These data provide new information about the dynamics of peptide-membrane interactions of a specific group of antiviral peptides, known for their potential as multipotent paramyxovirus antivirals.

Fusion Inhibitory Lipopeptides Engineered for Prophylaxis of Nipah Virus in Primates

“…Weight and temperature were measured after each anesthesia. Blood sampling was on days −1, 2, 4, 6,8,11,13,15,18,20,22,25, and 28 p.i. Hematology was analyzed using MS9-5 (Melet Schloesing) within 4 hours after collection in EDTA-containing tubes.…”

“…Conjugating cholesterol to an inhibitory peptide enhanced NiV antiviral activity up to 100-fold, by targeting the peptide to the plasma membrane [19,29,30]. We recently studied biophysical correlates of peptide antiviral properties using HPIV3 HRC-derived inhibitors [11,30] joined to the lipid by a flexible PEG linker, which is soluble in both aqueous and organic media and therefore in both plasma/extracellular fluids and membranes, nontoxic and nonimmunogenic [11,13].…”

“…Nipah virus F-mediated entry into target cells can be specifically targeted by fusion-inhibitory peptides that interfere with this initial step of viral entry by blocking formation of the 6-helix bundle. We have shown that fusion inhibitory peptide entry inhibitors, if conjugated to lipid moieties linked to the amino acid sequence by a flexible linker, can be highly effective inhibitors of NiV central nervous system (CNS) infection [10][11][12][13]. Exploiting the criteria that emerged from our previous biophysical studies, we designed a set of new lipopeptides with an amino acid sequence that confers greater stability to protease degradation and improved efficacy in vitro and in vivo.…”

Characterization and Synergistic Antimicrobial Evaluation of Lipopeptides from Bacillus amyloliquefaciens Isolated from Oil-Contaminated Soil

“…Polymyxin A is the example of lipopeptide with an antimicrobial activity which isolated from the soil bacterium Bacillus polymyxa [ 2 ]. Recently, several lipopeptides with diverse activities have been characterized, namely, as cytotoxic [ 3 ], antibacterial [ 4 , 5 ], antifungal [ 6 , 7 ], antiviral [ 8 , 9 ], plant pathogenicity [ 10 , 11 ], and anticancer [ 12 , 13 ]. Some of them have been commercially used as an antibacterial drug such as daptomycin [ 14 ], caspofungin [ 15 ], micafungin [ 16 ], vancomycin, and teicoplanin [ 17 ].…”

Peptide-Based Drugs and Drug Delivery Systems

“…Peptides corresponding to heptad repeat domains of viral glycoproteins have been shown to possess antiviral activity, which can be enhanced by conjugating them to lipids, thus targeting them to the plasma membrane, where fusion occurs. Augusto et al [ 15 ] provided new insight into the understanding of the mechanism of antiviral lipopeptides derived from the C -terminal heptad repeat of Paramyxovirus F protein. Among them, the peptide with a 24-unit PEG linker was conjugated to a cholesterol moiety, and was found to be the best membrane fusion inhibitory peptide; it also displayed a high affinity towards human peripheral blood mononuclear cells (PBMC), which could be used as an effective spreading vehicle of respiratory viruses traveling within the host to infect new tissues.…”