Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a causative agent of the pandemic coronavirus disease 2019 (COVID-19), which has resulted in over two million deaths worldwide to date. Diphyllin and diphyllinosides are known as natural blockers of cellular vacuolar ATPases, and so can act as inhibitors of the pH-dependent fusion of viral envelopes with host cell endosomal membranes. Such pH-dependent fusion is a critical early step during the SARS-CoV-2 replication cycle. Accordingly, the anti-SARS-CoV-2 profiles and cytotoxicities of diphyllin, diphyllinoside cleistanthin B, and two structurally related compounds, helioxanthin 8-1 and helioxanthin 5-4-2, are evaluated here using in vitro cell-based assay systems. Neither helioxanthin exhibits any obvious anti-SARS-CoV-2 effects in vitro. By contrast diphyllin and cleistanthin B do exhibit anti-SARS-CoV-2 effects in Vero cells, with respective 50% effective concentrations (EC50) values of 1.92 and 6.51 µM. Diphyllin displays anti-SARS-CoV-2 effect also in colorectal adenocarcinoma (CaCo-2) cells. Moreover, when diphyllin is added at various times post infection, a significant decrease in viral titer is observed in SARS-CoV-2-infected Vero cells, even at high viral multiplicities of infection. Importantly, neither diphyllin nor cleistanthin B are found cytotoxic to Vero cells in concentrations up to 100 µM. However, the cytotoxic effect of diphyllin is more pronounced in Vero E6 and CaCo-2 cells. Overall, our data demonstrate that diphyllin and diphyllin analogues might be perfected as anti-SARS-CoV-2 agents in future preclinical studies, most especially if nanomedicine approaches may be invoked to optimize functional drug delivery to virus infected cells.
Highlights
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), formerly known as 2019 novel coronavirus (2019-nCoV), is a causative agent of coronavirus disease 2019(COVID-19)
Diphyllin was synthesized by Apigenex (Prague, Czech Republic), cleistanthin B was obtained from WuXi AppTec (Tianjin, China), helioxanthin 8-1 and helioxanthin 5-4-2 were purchased from MedChemExpress (Stockholm, Sweden)
Diphyllin cytotoxicity was assessed in Vero, Vero E6, and CaCo-2 cells over the concentration range 0 to 100 μM at 48 h post treatment
Summary
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), formerly known as 2019 novel coronavirus (2019-nCoV), is a causative agent of coronavirus disease 2019(COVID-19). Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), formerly known as 2019 novel coronavirus (2019-nCoV), is a causative agent of coronavirus disease 2019. SARS-CoV-2 was firstly identified from the respiratory tract of pneumonia patients in Wuhan, China, in late December 2019, after which the virus spread to numerous other countries around the world over the few months [1]. On March 11, 2020, the World Health Organization (WHO) announced COVID-19 to be a new pandemic disease [1]. SARS-CoV-2 is an airborne virus, which is typically transmitted from person to person via respiratory droplets, transmission through contaminated surfaces is highly likely. The infection is asymptomatic or relatively mild, accompanied by fever, cough, shortness
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