Drug combination treatment as a strategy for inhibiting human adenovirus replication

Human adenoviruses (HAdVs) are ubiquitous human pathogens that infect the respiratory, ocular, and gastrointestinal tissues. Despite the severity of these infections in immunocompromised patients, there are no clinically approved antiviral medications to treat HAdV infections. Over the past decade, many compounds have been found to interfere with different parts of the HAdV replication cycle. One critical barrier to developing a successful HAdV therapy arises if the drug concentration required for antiviral efficacy is clinically unachievable or too toxic for patient use. This problem can be diminished by using a combination of drugs that function synergistically, potentially allowing the use of lower drug concentrations that are clinically achievable and/or exhibit acceptable toxicity profiles. In this exploratory study, we examined the antiviral activity of pairwise combinations of six drugs that have been previously shown to disrupt HAdV replication: ivermectin, digitoxin, deguelin, niclosamide, rosiglitazone, and remdesivir. Combinations of these drugs showed a stronger reduction in HAdV progeny production, protein expression, and genome replication efficiency compared to their individual effects. These experiments serve to illustrate the feasibility and benefits of drug combinations that synergize against HAdV replication.