Abstract
ABSTRACTAntivirals are urgently needed to combat the global SARS-CoV-2/COVID-19 pandemic, supplement existing vaccine efforts, and target emerging SARS-CoV-2 variants of concern. Small molecules that interfere with binding of the viral spike receptor binding domain (RBD) to the host angiotensin-converting enzyme II (ACE2) receptor may be effective inhibitors of SARS-CoV-2 cell entry. Here, we screened 512 pure compounds derived from natural products using a high-throughput RBD/ACE2 binding assay and identified (–)-hopeaphenol, a resveratrol tetramer, in addition to vatalbinoside A and vaticanol B, as potent and selective inhibitors of RBD/ACE2 binding and viral entry. For example, (–)-hopeaphenol disrupted RBD/ACE2 binding with a 50% inhibitory concentration (IC50) of 0.11 μM, in contrast to an IC50 of 28.3 μM against the unrelated host ligand/receptor binding pair PD-1/PD-L1 (selectivity index, 257.3). When assessed against the USA-WA1/2020 variant, (–)-hopeaphenol also inhibited entry of a VSVΔG-GFP reporter pseudovirus expressing SARS-CoV-2 spike into ACE2-expressing Vero-E6 cells and in vitro replication of infectious virus in cytopathic effect and yield reduction assays (50% effective concentrations [EC50s], 10.2 to 23.4 μM) without cytotoxicity and approaching the activities of the control antiviral remdesivir (EC50s, 1.0 to 7.3 μM). Notably, (–)-hopeaphenol also inhibited two emerging variants of concern, B.1.1.7/Alpha and B.1.351/Beta in both viral and spike-containing pseudovirus assays with similar or improved activities over the USA-WA1/2020 variant. These results identify (–)-hopeaphenol and related stilbenoid analogues as potent and selective inhibitors of viral entry across multiple SARS-CoV-2 variants of concern.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19)
While chemotherapy against the RNA polymerase and neutralizing antibody infusions are available, they depend on access to patient infusion resources
(13) to develop a high-throughput, 384 well plate-based assay to monitor the interaction of SARS-CoV-2 Spike receptor binding domain (RBD) with host ACE2 (Figure 2A)
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19). Since crossing into humans in late 2019, SARS-CoV-2 has continued to cause substantial human morbidity and mortality worldwide. CoV-2 vaccines are in development with several approved for use, access to these vaccines remains limited, in low and middle-income countries. Vaccine hesitancy and ongoing mutation of SARS-CoV-2 increase the risk of resistance to vaccine-induced immune responses. A significant gap in our therapeutic arsenal exists as no outpatient chemotherapy strategy is currently licensed to prevent infection or to combat mild to severe COVID-19. While chemotherapy against the RNA polymerase and neutralizing antibody infusions are available, they depend on access to patient infusion resources
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