Ultrapure and potent tannic acid as a pluripotent protease and influenza HA inhibitor against influenza virus infection

Background: Influenza viruses are fast-spreading respiratory pathogens that threaten public health and pose a colossal burden to the healthcare system. Current medications targeting viral enzymes struggle against resistant strains. Several human proteases mediate the proteolytic activation of viral hemagglutinin, whose cleavage is critically essential to virus penetration and propagation. Inhibiting these host proteases is thus a promising approach to prevent drug resistance. Materials & methods: We identified Pentarlandir^® ultrapure and potent tannic acid (UPPTA) as a versatile antiviral against host proteases crucial for influenza infection, the human airway trypsin-like protease as well as transmembrane serine protease 2 (hTMPRSS2) and even the viral neuraminidase. Results: Pentarlandir^® UPPTA inhibited the infection of circulating influenza viruses at sub-micromolar concentrations in vitro, including oseltamivir-resistant strains. Additionally, Pentarlandir^® UPPTA synergistically inhibited influenza viruses with oseltamivir carboxylate, showing excellent drug combination index and drug reduction index. Importantly, in a virus-challenged mice model, Pentarlandir^® UPPTA ameliorated infection-induced body weight loss and increased survival by halting infection-induced cytokine overproduction and subsequent lung damage. Conclusion: Taken together, with its virucidal activity against SARS-CoV2 virus, Pentarlandir^® UPPTA’s antiviral activity makes it a potential candidate against respiratory infections and an important player in the era of twindemic.