Effective inhibition of HCoV-OC43 and SARS-CoV-2 by phytochemicals in vitro and in vivo

•16 phytochemicals from medicinal plants traditionally used for respiratory-related illnesses tested against coronaviruses.•Five compounds showed promising antiviral activity against HCoV-OC43.•Three of these compounds also suppressed SARS-CoV-2 replication.•One compound, rottlerin, was tested in vivo and reduced SARS-CoV2-induced mortality in human ACE2-expressing K18 mice. Several coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human coronavirus OC43 (HCoV-OC43), can cause respiratory infections in humans. To address the need for reliable anti-coronavirus therapeutics, we screened 16 active phytochemicals selected from medicinal plants used in traditional applications for respiratory-related illnesses. An initial screen was completed using HCoV-OC43 to identify compounds that inhibit virus-induced cytopathic effect (CPE) and cell death inhibition. Then the top hits were validated in vitro against both HCoV-OC43 and SARS-CoV-2 by determining virus titer in cell supernatant and virus-induced cell death. Finally, the most active phytochemical was validated in vivo in the SARS-CoV-2-infected B6.Cg-Tg(K18-ACE2)2Prlmn/J mouse model. The phytochemicals lycorine (LYC), capsaicin, rottlerin (RTL), piperine and chebulinic acid (CHU) inhibited HCoV-OC43-induced cytopathic effect and reduced viral titres by up to 4 log. LYC, RTL and CHU also suppressed virus replication and cell death following SARS-CoV-2 infection. In vivo, RTL significantly reduced SARS-CoV-2-induced mortality by ∼40% in human angiotensin-converting enzyme 2 (ACE2)-expressing K18 mice. Collectively, these studies indicate that RTL and other phytochemicals have therapeutic potential to reduce SARS-CoV-2 and HCoV-OC43 infections.