molnupiravir and camostat

Topics: Adenosine Monophosphate; Administration, Oral; Alanine; Animals; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Neutralizing; Antiviral Agents; Clinical Trials as Topic; COVID-19; COVID-19 Drug Treatment; COVID-19 Vaccines; Cytidine; Depsipeptides; Dexamethasone; Drug Combinations; Drug Repositioning; Drug Synergism; Esters; Guanidines; Hospitalization; Host-Pathogen Interactions; Humans; Hydroxylamines; Internationality; Lactams; Leucine; Mice; National Institutes of Health (U.S.); Nitriles; Peptide Elongation Factor 1; Peptides, Cyclic; Proline; Protease Inhibitors; Ritonavir; RNA-Dependent RNA Polymerase; SARS-CoV-2; Serine Endopeptidases; Sodium-Glucose Transporter 2 Inhibitors; United States; Virus Replication

Three directly acting antivirals (DAAs) demonstrated substantial reduction in COVID-19 hospitalizations and deaths in clinical trials. However, these agents did not completely prevent severe illness and are associated with cases of rebound illness and viral shedding. Combination regimens can enhance antiviral potency, reduce the emergence of drug-resistant variants, and lower the dose of each component in the combination. Concurrently targeting virus entry and virus replication offers opportunities to discover synergistic drug combinations. While combination antiviral drug treatments are standard for chronic RNA virus infections, no antiviral combination therapy has been approved for SARS-CoV-2. Here, we demonstrate that combining host-targeting antivirals (HTAs) that target TMPRSS2 and hence SARS-CoV-2 entry, with the DAA molnupiravir, which targets SARS-CoV-2 replication, synergistically suppresses SARS-CoV-2 infection in Calu-3 lung epithelial cells. Strong synergy was observed when molnupiravir, an oral drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors: camostat, avoralstat, or nafamostat. The combination of camostat plus molnupiravir was also effective against the beta and delta variants of concern. The pyrimidine biosynthesis inhibitor brequinar combined with molnupiravir also conferred robust synergistic inhibition. These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of molnupiravir plus nirmatrelvir, the protease inhibitor found in paxlovid. Pharmacodynamic modeling allowed estimates of antiviral potency at all possible concentrations of each agent within plausible therapeutic ranges, suggesting possible

Topics: Antiviral Agents; COVID-19 Drug Treatment; Drug Combinations; Humans; Protease Inhibitors; Pyrimidines; SARS-CoV-2