Broad-Spectrum Antiviral Activity of the Sigma-1 Receptor Antagonist PB28 against Coronaviruses

Gaojie SONG¹Lingling Cheng¹Dapeng Li^2*Jia Cheng¹Shang Chao³Xiao Li³Ran Zhu^4*Cuiling Zhang^3*Junwei Li^5*

• ¹Jiujiang University, Jiujiang, China
• ²Jilin University, Changchun, China
• ³Chinese Academy of Agricultural Sciences, Beijing, China
• ⁴Yanbian University, Yanji, China
• ⁵Nanjing University of Chinese Medicine, Nanjing, China

The continuous evolution of coronaviruses poses persistent and severe threats to both human and animal health. While α-and β-coronaviruses mainly infect mammals, including humans, γ-coronaviruses predominantly infect poultry, causing substantial economic losses. Their rapid mutation rates and wide host tropism underscore the urgent demand for pan-coronavirus therapeutics. Here, we systematically investigated the antiviral potency and mechanism of action of PB28, a selective sigma-1 receptor antagonist, across α-, β-, and γ-coronaviruses. Molecular docking predicted a stable interaction between PB28 and the sigma-1 receptor. PB28 exhibits robust in vitro antiviral activity, effectively inhibiting the replication of β-coronaviruses (SARS-CoV-2 and its Beta, Delta, and Omicron variants; HCoV-OC43), α-coronaviruses (PEDV and TGEV), and γ-coronaviruses (IBV). Broad-spectrum antiviral efficacy is further validated by viral titration assays. In vivo, PB28 administration in K18-hACE2 mice infected with SARS-CoV-2 Delta and BALB/c mice infected with HCoV-OC43 led to significantly reduced viral loads, attenuated multi-organ pathology, and improved survival and body weight maintenance. In parallel, PB28 treatment in IBV-infected chicken embryos and neonatal chicks enhanced survival, supported embryogenesis, and alleviated tissue damage.Collectively, PB28 demonstrates cross-genus antiviral efficacy, likely mediated through modulation of the sigma-1 receptor. These findings highlight PB28 as a promising lead compound for the development of pan-coronavirus therapeutics.