Novel nucleocapsid protein-targeting phenanthridine inhibitors of SARS-CoV-2

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented in human history. As a major structural protein, nucleocapsid protein (NPro) is critical to the replication of SARS-CoV-2. In this work, 17 NPro-targeting phenanthridine derivatives were rationally designed and synthesized, based on the crystal structure of NPro. Most of these compounds can interact with SARS-CoV-2 NPro tightly and inhibit the replication of SARS-CoV-2 in vitro. Compounds 12 and 16 exhibited the most potent anti-viral activities with 50% effective concentration values of 3.69 and 2.18 μM, respectively. Furthermore, site-directed mutagenesis of NPro and Surface Plasmon Resonance (SPR) assays revealed that 12 and 16 target N-terminal domain (NTD) of NPro by binding to Tyr109. This work found two potent anti-SARS-CoV-2 bioactive compounds and also indicated that SARS-CoV-2 NPro-NTD can be a target for new anti-virus agents. [Display omitted] •Two novel NPro-targeted phenanthridine SARS-CoV-2 inhibitors were synthesized and inhibited SARS-CoV-2 in vitro.•The inhibitors target SARS-CoV-2 NPro by binding with Tyr109 in NTD according to SPR and mutagenesis assay.•NPro is a potential protein target for inhibiting the replication of SARS-CoV-2.