A Dual-Targeted, Long-Circulating, and Intelligent-Responsive Antiviral Agent Suppresses SARS-CoV-2 by Blocking Viral Entry and Replication.

Various natural drugs such as glycyrrhizic acid (GA), hesperidin (Hes), and baicalin (Bai) exhibit anti-SARS-CoV-2 potential but suffer from poor water solubility, short half-life, and low binding capacity to viral targets. Hence, a dual-targeted, long-circulating, ROS-responsive, and broad-spectrum antiviral inhibitor (mPAGHB) is designed through a strategy of "polymer-drug linkage". The mPAGHB suppresses SARS-CoV-2 through two "lines of defense", including extracellular inhibition of the "spike protein-angiotensin converting enzyme 2 (ACE2)" process and intracellular inhibition of the enzymatic activity of major protease. It exhibits higher affinity for spike protein (KD = 4.95 × 10-2 μM), excellent inhibition of Mpro activity (76.27 ± 5.94% inhibition), and improved inhibition for pseudovirus of SARS-CoV-2 and Omicron variants in cellular and animal assays. In addition, as an efficient generic strategy, the "polymer-drug linkage" strategy facilitates the rapid construction of antiviral inhibitors based on natural active ingredients for the outbreaks of viral public infections.