Investigating theobromine as a potential anti‐human coronaviral agent

Abstract

AbstractCoronaviruses (CoVs) have long been known to infect humans, mainly alpha‐CoV and beta‐CoV. The vaccines developed for SARS‐CoV‐2 are likely not effective against other coronavirus species, whereas the risk of the emergence of new strains that may cause the next epidemic/pandemic is high. The development of antiviral drugs that are effective across different CoVs represents a viable strategy for improving pandemic preparedness. In this study, we aim to identify pan‐coronaviral agents by targeting the conserved main protease (Mpro). For drug screening, the catalytic dyad of four human CoVs (HCoVs: SARS‐CoV‐2, and seasonal CoV NL63, OC43, and 229E) was targeted by molecular docking. The identified leading candidate theobromine, a xanthine derivative, was further tested in cell culture models of coronavirus infection. Theobromine binds strongly with the catalytic dyad (His41 and Cys144/145) of SARS‐CoV‐2 and HCoV‐NL63 Mpro, mildly with HCoV‐OC43, but not with HCoV‐229E. However, theobromine only shows dose‐dependent inhibition in Calu3 cells inoculated with SARS‐CoV‐2, but not in cells inoculated with seasonal CoVs. Theobromine exerts antiviral activity against coronavirus infections potentially through targeting Mpro. However, the antiviral potency is distinct among different CoVs.