Identification of Broad-Spectrum Antiviral Compounds by Targeting Viral Entry

Abstract

Viruses are a major threat to human health and economic well-being. In recent years Ebola, Zika, influenza, and chikungunya virus epidemics have raised awareness that infections can spread rapidly before vaccines or specific antagonists can be made available. Broad-spectrum antivirals are drugs with the potential to inhibit infection by viruses from different groups or families, which may be deployed during outbreaks when specific diagnostics, vaccines or directly acting antivirals are not available. While pathogen-directed approaches are generally effective against a few closely related viruses, targeting cellular pathways used by multiple viral agents can have broad-spectrum efficacy. Virus entry, particularly clathrin-mediated endocytosis, constitutes an attractive target as it is used by many viruses. Using a phenotypic screening strategy where the inhibitory activity of small molecules was sequentially tested against different viruses, we identified 12 compounds with broad-spectrum activity, and found a subset blocking viral internalisation and/or fusion. Importantly, we show that compounds identified with this approach can reduce viral replication in a mouse model of Zika infection. This work provides proof of concept that it is possible to identify broad-spectrum inhibitors by iterative phenotypic screenings, and that inhibition of host-pathways critical for viral life cycles can be an effective antiviral strategy.

Tilorone: a Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and beyond

“…It is expected that some changes and additions will occur with additional data and any interactions with the FDA or other regulatory agencies, but our preliminary data characterizing the activities and properties of tilorone already support many of the target parameters needed to move this forward as a broad-spectrum antiviral. Several recent articles have focused on repurposing of other classes of drugs in order to identify novel broad spectrum antivirals (49-51) and a few of these were found to impact viral entry (51). In addition, there are other broad spectrum antiviral drugs approved in Russia or elsewhere which may also be worthy of further assessment globally such as arbidol (52), triazavirin (53), cycloferon (54) and Kagocel (55).…”

Potential antiviral options against SARS-CoV-2 infection

“…It also showed broad-spectrum antiviral activity. It inhibited ZIKV, DENV, HCV, MERS-CoV, SARS-CoV, SARS-CoV-2, RRV, SINV, WNV, YFV, EBOV, LASV, RABV, VSV and HSV-1 viruses (https://doi.org/10.1101/2020.03.25.008482) (Boonyasuppayakorn et al, 2014;Dyall et al, 2014;Hulseberg et al, 2019;Mazzon et al, 2019;Sakurai et al, 2018;Zhou et al, 2017). It could be pursued as a potential anti-SARS-CoV-2 drug candidate.…”

The Use of Antimalarial Drugs against Viral Infection

“…While good results were obtained using quinine sulfate and MQ as antivirals, the same cannot be stated for halofantrine and lumefantrine, which failed in the inhibition of viral replication, based on the few studies conducted to date. Mazzon and colleagues, performing an in vitro screen of 2500 compounds, were able to describe inhibition activity of halofantrine on Semliki Forest virus (SFV) and DENV-2, but, due to the low selectivity index of the drug, further investigations were not conducted [134].…”

“…Flaviviridae BVDV(surrogate HCV) Artemisinin in vitro [187,188] Dihydroartemisinin in vitro [63] HCV Artemisinin in vitro [20][21][22] Artesunate in vitro [57] Chloroquine in vitro [148][149][150] ZIKV Mefloquine in vitro [130,131] Chloroquine in vitro [140,141] Amodiaquine in vitro [140] Atovaquone in vitro [166] DENV Quinine sulfate in vitro [66] Mefloquine in vitro [131] Halofantrine in vitro [134] Doxycycline in vitro [168,178] Amodiaquine in vitro [162] CHIKV Doxycycline in vitro [169] Chloroquine in vitro [37,138,139] Atovaquone in vitro [166] Togaviridae SFV Halofantrine in vitro [134] Rhabdoviridae VSV Doxycycline in vitro [170] Orthomyxoviridae IAV Quinine sulfate in vitro [70] In vivo (mouse) [67] Mefloquine in vitro [70] Doxycycline in vivo (mouse) [171] Chloroquine in vitro [159]…”