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

Abstract

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.