Dauricine interferes with SARS-CoV-2 variants infection by blocking the interface between RBD and ACE2.

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.

Computational and experimental studies of salvianolic acid A targets 3C protease to inhibit enterovirus 71 infection.

Hand, foot, and mouth disease (HFMD) is a common childhood infectious disease caused by enterovirus (EV) infection. EV71 is one of the major pathogens causing hand, foot, and mouth disease and is more likely to cause exacerbation and death than other enteroviruses. Although a monovalent vaccine for EV71 has been developed, there are no clinically available anti-EV71 specific drugs. Here, we performed virtual screening and biological experiments based on the traditional Chinese medicine monomer library. We identified a traditional Chinese medicine monomer, Salvianolic acid A (SA), a polyphenolic compound isolated from Salvia miltiorrhiza. Salvianolic acid A inhibits EV71 virus infection in a concentration-dependent manner, and its antiviral activity is higher than that of other reported natural polyphenols and has a high biosafety. Furthermore, molecular dynamics simulations showed that salvianolic acid A can anchor to E71, a member of the enzyme catalytic triad, and cause H40 to move away from the catalytic center. Meanwhile, molecular mechanics generalized born surface area (MMGBSA) and steered molecular dynamics (SMD) results showed that the P1 group of SA was most easily unbound to the S1 pocket of 3Cpro, which provided theoretical support to further improve the affinity of salvianolic acid A with 3Cpro. These findings suggest that salvianolic acid A is a novel EV71 3Cpro inhibitor with excellent antiviral activity and is a promising candidate for clinical studies.