Arbidol: A Broad-Spectrum Antiviral Compound that Blocks Viral Fusion

Abstract

Arbidol (ARB; ethyl-6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-indole-3-carboxylate hydrochloride monohydrate), is a Russian-made potent broad-spectrum antiviral with demonstrated activity against a number of enveloped and non-enveloped viruses. ARB is well known in Russia and China, although to a lesser extent in western countries. Unlike other broad-spectrum antivirals, ARB has an established molecular mechanism of action against influenza A and B viruses, which is different from that of available influenza antivirals, and a more recently established mechanism of inhibition of hepatitis C virus (HCV). For both viral infections the anti-viral mechanism involves ARB inhibition of virus-mediated fusion with target membrane and a resulting block of virus entry into target cells. However, ARB inhibition of fusion exploits different ARB modalities in case of influenza viruses or HCV. This review aims to summarize the available evidence of ARB effects against different groups of viruses, also, to compare various aspects of ARB anti-fusion mechanisms against influenza virus and HCV (with reference to different stringency of pH-dependence of these two viral fusogens) and to discuss further prospects for ARB and its improved derivatives of the parent compounds.

Low pH-dependent Hepatitis C Virus Membrane Fusion Depends on E2 Integrity, Target Lipid Composition, and Density of Virus Particles

“…This is the first direct description of HCV fusion characteristics in a genotype 2a context using physio-pathologically relevant HCVcc particles. Moreover, assessing the interference of arbidol, a small fusion inhibitor molecule recently described by us as a potential HCV entry inhibitor (52)(53)(54), further confirmed the utility of the HCVcc fusion assay for the characterization of HCV fusion inhibitors (Fig. 2).…”

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

“…Arbidol (umifenovir) is a broad-spectrum antiviral against a number of enveloped and nonenveloped viruses such as influenza, respiratory syncytial (RSV), adenovirus, Coxsackie B5, parainfluenza, Ebola (EBOV), and hepatitis B and C (14)(15)(16)(17)(18)(19)(20). Arbidol demonstrates broad activity against diverse strains and subtypes of influenza A and B viruses and is effective in mice infected with A/California/07/2009 (H1N1), A/Puerto Rico/8/1934 Significance Influenza virus is an important human pathogen.…”

“…(H1N1), and A/Aichi/2/1969 (H3N2) influenza A viruses (14)(15)(16)(17)(18)21). Arbidol is used primarily as an over-the-counter drug in Russia and China for prophylaxis and treatment of acute respiratory infections including influenza, but has not yet gained acceptance in other countries.…”

“…One major drawback of Arbidol is that a large dose must be administered to achieve peak plasma concentration and therapeutic efficacy. To understand the molecule mechanism for its broad-spectrum inhibition of influenza viruses, various in vitro assays have been reported (14,(22)(23)(24), From the reported K d s with H1, H2, H3, H4, and H5 HA strains, Arbidol binds with higher affinity to group 2 HAs (K d s = 5.6-7.9 μM) than to group 1 HAs (K d s = 18.8-44.3 μM) (23). Mechanistically, Arbidol has been shown to increase influenza virus HA stability and prevent the low pH-induced HA transition to its fusogenic state, thereby blocking infection at one of the two key steps in cell entry, i.e., at viral fusion.…”

Lipid Involvement in Viral Infections: Present and Future Perspectives for the Design of Antiviral Strategies

“…As a first approach to inhibit enveloped virus multiplication, the functions of lipids incorporated into the viral particle can be targeted by chemical compounds or even by antibodies [161]. This is the case of broad-spectrum antivirals, − some of them already licensed for human use, such as arbidol [162][163][164] −, or inhibitors of membrane fusion [3]. Impairment of viral fusion can be achieved also by targeting viral machinery involved in this process, a strategy currently assayed for HIV treatment [165].…”