Abstract
Influenza A viral (IAV) fusion peptides are known for their important role in viral-cell fusion process and membrane destabilization potential which are compatible with those of antimicrobial peptides. Thus, by replacing the negatively or neutrally charged residues of FPs with positively charged lysines, we synthesized several potent antimicrobial peptides derived from the fusogenic peptides (FPs) of hemagglutinin glycoproteins (HAs) of IAV. The biological screening identified that in addition to the potent antibacterial activities, these positively charged fusion peptides (pFPs) effectively inhibited the replication of influenza A viruses including oseltamivir-resistant strain. By employing pseudovirus-based entry inhibition assays including H5N1 influenza A virus (IAV), and VSV-G, the mechanism study indicated that the antiviral activity may be associated with the interactions between the HA2 subunit and pFP, of which, the nascent pFP exerted a strong effect to interrupt the conformational changes of HA2, thereby blocking the entry of viruses into host cells. In addition to providing new peptide “entry blockers”, these data also demonstrate a useful strategy in designing potent antibacterial agents, as well as effective viral entry inhibitors. It would be meaningful in treatment of bacterial co-infection during influenza pandemic periods, as well as in our current war against those emerging pathogenic microorganisms such as IAV and HIV.
Highlights
To date, influenza A viruses (IAV) are one of the critical human respiratory pathogens that cause morbidity and mortality seasonally, and create serious public fear and economic loss worldwide
Given the highly conserved region of fusogenic peptides (FPs) in the hemagglutinin glycoproteins (HAs) (Table 1) and the critical role in fusogenic process [7], we evaluated their antiviral activity against influenza viral strains of A/Puerto Rico/8/34 (H1N1) and A/Aichi/2/68 (H3N2) by using virus cytopathic effect (CPE) inhibition assay
To confirm the antiviral activities from CPE test and RT-PCR measurement, we evaluated the antiviral effect of HA-FP-2-1 were 144.4 μg/mL (HA-FP-1) toward A/Puerto Rico/8/34 (H1N1) viral strain by using virus titer reduction assay (Fig 1B) and enzyme-linked immunosorbent assay (ELISA) (Fig 1C)
Summary
Influenza A viruses (IAV) are one of the critical human respiratory pathogens that cause morbidity and mortality seasonally, and create serious public fear and economic loss worldwide. Three modes of action of antimicrobial peptides have been proposed with respect to viruses: direct virolysis, inhibition of transcription from the long terminal repeat (LTR) promoter, and block of cell entry by binding to cell surface receptors [4]. This means that a novel antiviral agent could be PLOS ONE | DOI:10.1371/journal.pone.0138426. This means that a novel antiviral agent could be PLOS ONE | DOI:10.1371/journal.pone.0138426 September 18, 2015
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