Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19)

Abstract

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signals an urgent need for an expansion in treatment options. In this study, we investigated the anti-SARS-CoV-2 activities of 22 antiviral agents with known broad-spectrum antiviral activities against coronaviruses and/or other viruses. They were first evaluated in our primary screening in VeroE6 cells and then the most potent anti-SARS-CoV-2 antiviral agents were further evaluated using viral antigen expression, viral load reduction, and plaque reduction assays. In addition to remdesivir, lopinavir, and chloroquine, our primary screening additionally identified types I and II recombinant interferons, 25-hydroxycholesterol, and AM580 as the most potent anti-SARS-CoV-2 agents among the 22 antiviral agents. Betaferon (interferon-β1b) exhibited the most potent anti-SARS-CoV-2 activity in viral antigen expression, viral load reduction, and plaque reduction assays among the recombinant interferons. The lipogenesis modulators 25-hydroxycholesterol and AM580 exhibited EC50 at low micromolar levels and selectivity indices of >10.0. Combinational use of these host-based antiviral agents with virus-based antivirals to target different processes of the SARS-CoV-2 replication cycle should be evaluated in animal models and/or clinical trials.

Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial

“…Among IFNs, the most reductive effects on viral load belonged to IFN β-1a and IFN β-1b. However, IFN β-1b showed highest potency and selectivity index against SARS-COV-2 [22] .…”

SARS-CoV-2 Requires Cholesterol for Viral Entry and Pathological Syncytia Formation

“…Apilimod, a PIKFYVE inhibitor and promising therapeutic in multiple SARS-CoV-2 models (Kang et al, 2020;Riva et al, 2020) including heterokaryon assays tested herein ( Figures 3E; S3B), prevented pseudoparticle entry at nanomolar concentrations ( Figure 7B). By contrast, 25-hydroxycholesterol, which lowers plasma membrane cholesterol by redirection to the cell interior (Abrams et al, 2020;Im et al, 2005;Wang et al, 2020;Yuan et al, 2020;Zhu et al, 2020b;Zu et al, 2020), had no effect ( Figure 7C). However, MBCD, which directly "strips" plasma membrane cholesterol without engaging intracellular targets (Zidovetzki and Levitan, 2007), blocked virus entry ( Figure 7D).…”

JAK-inhibitor and type I interferon ability to produce favorable clinical outcomes in COVID-19 patients: a systematic review and meta-analysis

“…These interferons have been found to have positive therapeutic effects in the treatment of viral infections including hepatitis [14], and coronaviruses such as SARS and MERS [15,16]. One investigation assessed Type I recombinant interferon to be one of the most potent anti-SARS-CoV-2 antiviral agents [17]. Additionally, a recent investigation revealed that several severe cases of COVID-19 presented with a rare, X-chromosome lossof-function mutation that impaired Type I interferon response [18], while another demonstrated an association between COVID-19 severity and Type I interferon deficiency [19].…”