Synthesis and anti-SARS-CoV-2 activity and mechanism research of lycorine derivatives
We designed and synthesized eighteen lycorine derivatives with five different structural types,and evaluated their antiviral activities on a HCoV-OC43-infected H460 cell model.Structure-activity relationships suggested that the introduction of appropriate substituents on the 6N atom of lycorine was beneficial to activity.Compound 6a gave a good activity with the half effective concentration(EC50)and selectivity index(SI)values of 2.36 μmol·L-1 and 16.52,respectively.Surface plasmon resonance(SPR)result indicated that 6a might target the non-structural protein 12(NSP12)subunit in RNA-dependent RNA polymerase(RdRp)of SARS-CoV-2 with the dissociation constant(KD)value of 1.36 μmol·L-1.Molecular docking indicated that 6a might act on nidovirus RdRp-associated nucleotidyltransferase(NiRAN)catalytic center of NSP12,distinct from the mechanism of nucleoside-like drugs such as remdesivir.This study provides scientific data for the development of lycorine derivatives into a new class of anti-SARS-CoV-2 small molecule inhibitors.
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维普
