High-affinity, broad-spectrum, "centipede-like" multi-branched drug conjugates, anchored to the S protein, for blocking coronavirus infection

Abstract

Over the past two decades, various coronaviruses have posed a severe threat to human life and health, with the spike protein (S protein) being a critical protein for infecting host cells. Glycyrrhizic acid (GA), as a natural drug, can inhibit the infection of coronaviruses by binding to the receptor-binding domain (RBD) of the S protein. However, issues like poor water solubility and weak binding affinity with the S protein have hindered its further application. Therefore, drawing inspiration from the biological structure of centipedes, a ROS-responsive multi-branched drug conjugate (ODPAG) was constructed through a "polymer-drug linkage" strategy using dextran as the backbone and GA as the active "claw". ODPAG exhibited drug loading of 22.0 ± 0.2% (OD_40kPAG) and 19.7 ± 0.1% (OD₄₅₀kPAG), showing ROS responsiveness with a half-life 6.4 times that of GA (OD_40kPAG) and 5.4 times longer (OD₄₅₀kPAG). In in vitro antiviral experiments, ODPAG exhibited an enhanced binding affinity to the S protein, with IC₅₀ values of 1.33 μM (OD_40kPAG) and 0.89 μM (OD_450kPAG) against SARS-CoV-2 pseudovirus, demonstrating exceptional antiviral efficacy. These results collectively indicate that ODPAG can block coronavirus infection by binding to the S protein, exhibiting significant potential in addressing the current challenges posed by the novel coronavirus. Additionally, the "polymer-drug conjugate" strategy employed in this process is efficient, cost-effective, and offers new insights for combating future emergent coronaviruses.