Inhibition of Human Coronaviruses by Antimalarial Peroxides

Area of Science:

• Pharmacology
• Virology
• Medicinal Chemistry

Background:

• The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic necessitates the search for effective treatments.
• Antimalarial peroxides, including ozonides, have demonstrated antiviral and anticancer properties.
• Drug repurposing offers a potential strategy for rapid development of COVID-19 therapies.

Purpose of the Study:

• To evaluate the in vitro antiviral activity of artesunate (AS) and two ozonides (OZ418, OZ277) against human alpha-coronavirus NL63, beta-coronavirus OC43, and SARS-CoV-2.
• To determine the selectivity index (SI) and efficacy of these compounds in various cell lines.
• To explore the potential of ozonides as repurposed drugs for coronavirus infections.

Main Methods:

• In vitro antiviral assays were performed using artesunate, OZ418, and OZ277 against NL63, OC43, and SARS-CoV-2 in Vero, MK2, human foreskin fibroblast, and Calu-3 cell lines.
• Selectivity index (SI) and EC50 values were calculated to assess compound efficacy and toxicity.
• Drug combination studies with OZ418 and remdesivir were conducted against SARS-CoV-2.

Main Results:

• OZ418 exhibited the best selectivity index against NL63 in Vero and MK2 cells.
• Artesunate showed the highest cell-associated SI against OC43 in human foreskin fibroblasts.
• Artesunate did not inhibit SARS-CoV-2; OZ418 and OZ277 showed moderate EC50 values against SARS-CoV-2 in Calu-3 cells, with OZ418 having a higher SI.
• Combination of OZ418 with remdesivir improved SARS-CoV-2 inhibition.
• Another ozonide, OZ439, showed efficient SARS-CoV-2 inhibition in Vero cells but higher toxicity in Calu-3 cells.

Conclusions:

• Ozonides, particularly OZ418, demonstrate potential for repurposing against coronaviruses, including SARS-CoV-2, with cell-type dependent activity and SI.
• Drug combinations, such as OZ418 with remdesivir, may enhance efficacy against SARS-CoV-2.
• Further in vivo studies are warranted to confirm the therapeutic potential of ozonides for viral infections, considering factors like sustained tissue suppression.