ABSTRACT
Influenza can cause respiratory infections, leading to significant morbidity and mortality in humans. While current influenza vaccines offer varying levels of protection, there remains a pressing need for effective antiviral drugs to supplement vaccine efforts. Currently, the FDA-approved antiviral drugs for influenza include oseltamivir, zanamivir, peramivir, and baloxavir marboxil. These antivirals primarily target the virus, making them vulnerable to drug resistance. In this study, we evaluated the efficacy of the neuraminidase inhibitor, oseltamivir, against probenecid, which targets the host cells and is less likely to engender resistance. Our results show that probenecid has superior antiviral efficacy compared to oseltamivir in both in vitro replication assays and in vivo mouse models of influenza infection.
Subject(s)
Influenza Vaccines , Influenza, Human , Humans , Animals , Mice , Oseltamivir/pharmacology , Oseltamivir/therapeutic use , Probenecid/pharmacology , Probenecid/therapeutic use , Influenza Vaccines/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Enzyme Inhibitors/pharmacology , Virus Replication , Neuraminidase , Drug Resistance, ViralABSTRACT
RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. We investigated if probenecid, an FDA-approved and safe urate-lowering drug that inhibits organic anion transporters (OATs) has prophylactic or therapeutic efficacy to inhibit RSV replication in three epithelial cell lines used in RSV studies, i.e., Vero E6 cells, HEp-2 cells, and in primary normal human bronchoepithelial (NHBE) cells, and in BALB/c mice. The studies showed that nanomolar concentrations of all probenecid regimens prevent RSV strain A and B replication in vitro and RSV strain A in vivo, representing a potential prophylactic and chemotherapeutic for RSV.
Subject(s)
COVID-19 , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human , Animals , Mice , Probenecid/pharmacology , Probenecid/therapeutic use , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus, Human/genetics , SARS-CoV-2 , Virus ReplicationABSTRACT
Effective vaccines are slowing the COVID-19 pandemic, but SARS-CoV-2 will likely remain an issue in the future making it important to have therapeutics to treat patients. There are few options for treating patients with COVID-19. We show probenecid potently blocks SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Furthermore, we demonstrate that plasma concentrations up to 50-fold higher than the protein binding adjusted IC90 value are achievable for 24 h following a single oral dose. These data support the potential clinical utility of probenecid to control SARS-CoV-2 infection in humans.
