Surfactin Inhibits Membrane Fusion during Invasion of Epithelial Cells by Enveloped Viruses

Abstract

Because membrane fusion is a crucial step in the process by which enveloped viruses invade host cells, membrane fusion inhibitors can be effective drugs against enveloped viruses. We found that surfactin from can suppress the proliferation of porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV) in epithelial cells at a relatively low concentration range (15 to 50 μg/ml), without cytotoxicity or viral membrane disruption. Membrane fusion inhibition experiments demonstrate that surfactin treatment significantly reduces the rate at which the virus fuses to the cell membrane. Thermodynamic experiments show that the incorporation of small amounts of surfactin hinders the formation of negative curvature by lamellar-phase lipids, suggesting that surfactin acts a membrane fusion inhibitor. A fluorescent lipopeptide similar to surfactin was synthesized, and its ability to insert into the viral membrane was confirmed by spectroscopy. experiments have shown that oral administration of surfactin to piglets protects against PEDV infection. In conclusion, our study indicates that surfactin is a membrane fusion inhibitor with activity against enveloped viruses. As the first reported naturally occurring wedge lipid membrane fusion inhibitor, surfactin is likely to be a prototype for the development of a broad range of novel antiviral drugs. Membrane fusion inhibitors are a rapidly emerging class of antiviral drugs that inhibit the infection process of enveloped viruses. They can be classified, on the basis of the viral components targeted, as fusion protein targeting or membrane lipid targeting. Lipid-targeting membrane fusion inhibitors have a broader antiviral spectrum and are less likely to select for drug-resistant mutations. Here we show that surfactin is a membrane fusion inhibitor and has a strong antiviral effect. The insertion of surfactin into the viral envelope lipids reduces the probability of viral fusion. We also demonstrate that oral administration of surfactin protects piglets from PEDV infection. Surfactin is the first naturally occurring wedge lipid membrane fusion inhibitor that has been identified and may be effective against many viruses beyond the scope of this study. Understanding its mechanism of action provides a foundation for the development of novel antiviral agents.

Synthetic surfactin analogues have improved anti-PEDV properties

“…In a previously published study we demonstrated that surfactin has antiviral activity as membrane fusion inhibitor [3]. In order to improve the viral envelope selectivity of surfactin, we designed 10 analogues with altered peptide amino acids, but kept the length of fatty acid chain of 16 carbon atoms.…”

“…SLP5 also has two fewer hydrophobic amino acids than surfactin, this reduces the cost of synthesis while having little effect on antiviral activity. Since surfactin has been shown to protect piglets from PEDV challenge [3], the in vivo antiviral properties of surfactin analogues needs to be tested. Furthermore, with respect to the future use of synthetic surfactins to control or ameliorate infection in pigs, the broader spectrum physiological activities of surfactin analogues needs further study and side effects beyond hemolytic toxicity need to be explored.…”

“…Surfactin has antiviral activity against a variety of enveloped viruses, including herpes simplex virus (HSV-1, HSV-2), vesicular stomatitis virus (VSV), simian immunodeficiency virus (SIV) and Newcastle disease virus (NDV) [1,2]. We recently demonstrated that surfactin exerts its antiviral effects by inhibiting viral membrane fusion [3]. Membrane fusion between the viral envelope and the cell membrane is essential for enveloped viruses to invade host cells.…”

Peptidoglycan associated cyclic lipopeptide disrupts viral infectivity

“…Over the last two decades, surfactin has been shown to be anti-bacterial, anti-fungal, and anti-viral (11, 12, 17–19). Mechanistically, surfactin’s broad anti-microbial efficacy has been linked to disruption of lipid membranes (13).…”

“…Mechanistically, surfactin’s broad anti-microbial efficacy has been linked to disruption of lipid membranes (13). However, more recently, researchers described surfactin’s efficacy against the animal CoV porcine epidemic diarrhea virus (PEDV), and suggested that surfactin inhibited viral-host membrane fusion (19). In contrast to the PEDV results, we found that surfactin treatment disrupted virion integrity, exposing the viral RNA to RNase I mediated degradation (Fig.…”