Research Article: Synthetic surfactin analogues have improved anti-PEDV properties

Date Published: April 11, 2019

Publisher: Public Library of Science

Author(s): Lvfeng Yuan, Shuai Zhang, Jie Peng, Yuchen Li, Qian Yang, Yongchang Cao.

http://doi.org/10.1371/journal.pone.0215227

Abstract

Surfactin has antiviral activity against various enveloped viruses by inhibiting viral membrane fusion. However, the potential utility of surfactin as an antiviral drug is limited by its cytotoxicity. In this study, 10 surfactin analogues were obtained by chemical synthesis and evaluated to determine their anti-PEDV activities, hemolytic activities, and critical micelle concentrations. The main goal of our study was to develop a safer drug; a surfactin analogue with high anti-PEDV activity and low hemolytic activity. Compared with surfactin, one of the analogues we developed, SLP5, has lower hemolytic activity, with the same antiviral activity. The selectivity index of SLP5 is 52, while the SI for surfactin is 4, in other words, the safe and effective concentration range of SLP5 is 12 times greater than that of surfactin. Like surfactin, SLP5 has a direct antiviral effect on PEDV. Structurally, SLP5 is a linear lipopeptide with three carboxyl groups. Surfactin derivatives similar to SLP5 could be obtained by lactone bond hydrolyzation of surfactin, as well as total synthesis.

Partial Text

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. Surfactin can act directly on virus particles by insertion into the viral envelopes’ lipid bilayer and thereby reduce the membrane fusion rate. In addition, since the lipid components of viral envelopes are provided by the host cell, their composition, structure, and function are widely similar in the enveloped viruses. Surfactin has antiviral activity against numerous enveloped viruses, and it has promise as a broad-spectrum antiviral reagent, however, the effective dose range of surfactin is narrow, merely 4 x the antiviral concentration causes hemolysis and cytotoxicity. In this study we compared chemically synthesized surfactin analogues to determine future directions for surfactin modification.

Wedge-shaped lipids in which the hydrophilic head has a larger cross-sectional area than the hydrophobic tail, are potential membrane fusion inhibitors [20, 21]. In a recent study of rigid amphipathic fusion inhibitors, compounds with deoxyribose or acetate as hydrophilic moieties had anti-HSV effects [22]. In addition, a recent study on antimicrobial activity of synthetic lipopeptides reported that lipopeptides with two to four positive charges and 16 carbon atoms in the lipid chain have potent antimicrobial activity [23]. Fatty acid chain length from 8 to 16 carbon atoms is positively correlated with antimicrobial activity, but is also positively correlated with hemolytic activity and membrane selectivity [24]. These factors must be considered in the design of new lipopeptides, and the structure-function relationships warrant further study. Here we investigated lipopeptides containing two and three negative charges, and two positive charges, all with a fatty acid chain of 16 carbon atoms. All of these lipopeptides had antiviral activity.

 

Source:

http://doi.org/10.1371/journal.pone.0215227

 

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