Crystal structure of F10 core protein from Mpox virus reveals its potential inhibitors

Mpox virus (MPXV), a member of Poxviridae family, causes a rare zoonotic disease. According to the most recent data, over 15,600 cases and 537 deaths of human mpox have been reported. The MPXV complete RNA polymerase (RNAP), which is responsible for the entire early transcriptional cycle, comprises the RNAP core enzyme and essential factors including viral early transcription factor (VETF), nucleoside triphosphate phosphohydrolase I (NPH-I), RNA polymerase-associated protein (Rap94), and F10 core protein. The dimeric F10 core protein stabilizes the N-terminal region of Rap94, and the C-terminal domain of NPH-I, functioning as a structural clamp that enhances the stability of the RNAP complex. Here, we determined the crystal structure of the F10 core protein at a high resolution of 1.5 Å, and identified a cavity between the F10 core protein and NPH-I through superimposition of the MPXV F10 core protein and the vaccinia virus (VACV) RNAP. We further conducted a virtual screening based on this cavity, and identified 28 compounds as potential MPXV inhibitors. To the best of our knowledge, this is the first study to screen for inhibitors targeting MPXV RNAP. Our study may facilitate the development of novel ways for the discovery of anti-MPXV compounds against emerging pathogens. •A high-resolution crystal structure of MPXV F10 core protein was determined for the first time.•A structural cavity between F10 and NPH-I was first identified which may serve as the accommodation site for MPXV inhibitors.•A number of potential F10 inhibitors were obtained by virtual screening based on the cavity.•This work may be helpful to developing novel anti-MPXV compounds and strategies.