The continued viral evolution results in the emergence of various SARS-CoV-2 variants, such as delta or omicron, that are partially resistant to current vaccines and antiviral medicines, posing an increased risk to global public health and raising the importance of continuous development of antiviral medicines. Inhibitor screening targeting the interactions between the viral spike proteins and their human receptor ACE2 represents a promising approach for drug discovery. Here, we demonstrate that the evolutionary trend of the SARS-CoV-2 variants is associated with increased electrostatic interactions between S proteins and ACE2. Virtual screening based on the ACE2-RBD binding interface identified nine monomers of Traditional Chinese medicine (TCM). Furthermore, live-virus neutralization assays revealed that Dauricine, one of the identified monomers, exhibited an antiviral activity with an IC50 range of 18.2 to 33.3 μM for original strain, Delta, and Omicron strains, respectively. The computational study showed that the polycyclic and methoxy groups of Dauricine adhere to the RBD surface through π-π and electrostatic interactions. The discovery of Dauricine is a successful attempt to target viral entry, which will not only help society to respond quickly to viral variants, but also accelerate variant drug development thereby reducing the pressure on health authorities to respond to outbreaks.
Keywords: ACE2; Dauricine; SARS-CoV-2; Spike protein; Variant.
Copyright © 2023. Published by Elsevier B.V.