Discovery of a novel broad-spectrum inhibitor against influenza virus A.

Abstract

The pandemic of influenza A virus (IAV) is on the rise worldwide, however, drug resistance to anti-influenza drugs has been widely found. The viral mutation of IAV highlights the necessitate for discovery of new antiviral agents with broad-spectrum efficacy. Arbidol, an effective pharmaceutical against IAV and other viruses, inhibits viral fusion by targeting a conserved binding region across multiple virus types. The binding area of Arbidol is conserved towards many types of viruses, however, the structural characteristics of Arbidol make it possible human ether-α-go-go related gene (hERG) potassium channel inhibitory. The risk of arrhythmias by Arbidol will limit its further application. Therefore, developing new broad-spectrum antiviral drugs with reduced side effects based on Arbidol's scaffold is imperative. In this study, 50 natural products were screened for effective universal antiviral drug based on the structure-activity relationship between Arbidol and hemagglutinin (HA). Due to the structural characters of Arbidol related to hERG inhibition, the inhibitory activity of Arbidol on hERG channels were also analyzed by patch clamp technology and molecular docking for toxicity and safety evaluation of drug screening and development. The IC50 of Arbidol to hERG was 0.3030 µM. The results showed that Glycyrrhetinic acid has lower binding energy than Arbidol in the binding site. The molecular structure of Glycyrrhetinic acid is more flexible, which avoids significant interactions with hERG. These findings highlight glycyrrhetinic acid as a promising broad-spectrum anti-IAV candidate drug.