Sigma-1 Receptor-Targeting Compounds Show Antiviral Activity Across Multiple Coronavirus Models

Over the past two decades, coronaviruses have caused three major public health crises, including the epidemics of SARS-CoV, MERS-CoV, and SARS-CoV-2. Following the outbreak of SARS-CoV-2, several antiviral drugs have been approved for the treatment of COVID-19. However, the high mutation rate of SARS-CoV-2 has led to the emergence of multiple variants, some of which can escape vaccine-induced immunity and develop resistance to virus-targeted drugs. Viruses rely on host cell mechanisms to complete replication and transmission. Host-directed therapy is an emerging strategy that inhibits infection by targeting host cell factors essential for pathogen replication. Interventions targeting host factors have been proven effective in limiting viral infections and have the potential to reduce the risk of drug resistance. Our previous study found that the sigma-1 receptor (σ1R) is involved in the autophagic process mediated by the SARS-CoV-2 non-structural protein NSP6, suggesting that σ1R may serve as a therapeutic target against SARS-CoV-2. In this study, we found that the σ1R antagonists BD-1047 and σ1RA1 inhibited SARS-CoV-2 and its variants in vitro and showed antiviral activity in vivo. At the cellular level, these compounds also inhibited porcine epidemic diarrhea virus (PEDV) and infectious bronchitis virus (IBV), indicating cross-model antiviral activity. BD-1047 further showed antiviral activity against HCoV-OC43 in both in vitro and in vivo models. In addition, Ocaperidone, identified through computer-aided screening, exhibited protective effects against SARS-CoV-2 and HCoV-OC43 in both cell-based and mouse models. Collectively, these findings support σ1R as a host-associated antiviral target candidate and provide several compounds for further optimization and mechanistic investigation.