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Commentary on Wolf, M.C.; Freiberg, A.N.; Zhang, T.; Akyol-Ataman, Z.; G rock, A.; Hong, P.W.; Li, J.; Watson, N.F.; Fang, A.Q.; Aguilar, H.C.;
In contrast to several widely used antibiotics, antiviral drugs typically target a single virus. The rising number of diverse emerging and endemic viral diseases that pose a significant health risk to human populations underscores the need to develop broad-spectrum antivirals. However, the few broad-spectrum antivirals that are licensed have limited potency and are poorly tolerated [
LJ001 is an aryl methyldiene rhodanine derivative that was found during a high-throughput cell-based screen for inhibitors of Nipah virus (NiV) entry using a vesicular stomatitis virus (VSV) luciferase reporter pseudotype system. LJ001 caused minimal cellular toxicity at
To this point, the activity of LJ001 resembled that of other inhibitors that act at very early stages of the viral lifecycle. However, it became evident that LJ001 showed antiviral activity not just against Nipah virus, but also against an impressive array of viruses including representatives of the filoviridae, orthomyxoviridae, arenaviridae, bunyaviridae, paramyxoviridae, flaviviridae, retroviridae, poxviridae and rhbdoviridae, but not against members of the adenoviridae, picornoviridae and reoviridae. As a result, its antiviral activity was independent of the viral glycoprotein responsible for mediating virus entry. The only unifying, structural feature evident amongst the diverse viruses that were inhibited by LJ001 is the presence of a viral membrane: LJ001 inhibited all enveloped viruses tested, but failed to inhibit nonenveloped viruses. Aided by its intrinsic fluorescence, the authors showed that LJ001 associates with liposomes, and that liposomes can compete with NiV-pseudotyped VSV for LJ001 unless virions were pretreated with LJ001 before addition of liposomes. The authors suggest that LJ001 intercalates into viral membranes in an essentially irreversible manner, preventing membrane fusion in a manner that is independent of the viral membrane fusion protein. To further support a proposed viral glycoprotein-independent mechanism of action, the authors attempted to generate resistant HIV mutants through serial passaging, yet resistant virus failed to develop after four weeks. Longer passaging studies as well as the use of additional strains of the viruses tested thus far may provide clues for a mechanism of action and address the important issue of whether resistance can be generated. Another unanswered question is whether LJ001 intercalates preferentially into viral membranes, or whether it associates equally well with any lipid bilayer regardless of specific protein or lipid content. Without some degree of membrane specificity, it is difficult to envisage how LJ001 will achieve high enough levels
Though LJ001 associates with both viral and host membranes, it is only the viral membrane whose function appears to be impaired: LJ001 inhibits virus-cell fusion, but it fails to inhibit cell-cell fusion reactions mediated by the same viral glycoprotein. The authors hypothesize that this is due to the fact that host membranes are continually remodeled and can repair themselves by metabolizing or extracting membrane-active agents, thus escaping gross membrane perturbation [
Other membrane targeting broad-spectrum antivirals have been developed with varying degrees of success. Cosalane is thought to associate with viral membranes and showed activity against HIV and some herpes viruses
The discovery of LJ001 serves as an important proof of principle for a more global and unbiased approach towards the screening of antiviral compounds. While traditional