LAUSR

Outbreaks of coronaviruses (CoVs), especially severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), have posed serious threats to humans and animals, which urgently calls for effective broad‐spectrum antivirals. RNA‐dependent RNA polymerase (RdRp) plays an essential role in viral RNA synthesis and is an ideal pan‐coronaviral therapeutic target. Herein, based on cryo‐electron microscopy and biochemical approaches, gossypol (GOS) is identified from 881 natural products to directly block SARS‐CoV‐2 RdRp, thus inhibiting SARS‐CoV‐2 replication in both cellular and mouse infection models. GOS also acts as a potent inhibitor against the SARS‐CoV‐2 variant of concern (VOC) and exerts same inhibitory effects toward mutated RdRps of VOCs as the RdRp of the original SARS‐CoV‐2. Moreover, that the RdRp inhibitor GOS has broad‐spectrum anti‐coronavirus activity against alphacoronaviruses (porcine epidemic diarrhea virus and swine acute diarrhea syndrome coronavirus), betacoronaviruses (SARS‐CoV‐2), gammacoronaviruses (avian infectious bronchitis virus), and deltacoronaviruses (porcine deltacoronavirus) is showed. The findings demonstrate that GOS may serve as a promising lead compound for combating the ongoing COVID‐19 pandemic and other coronavirus outbreaks.