Assessment of combined antiviral drug treatment against selected α-, β-, and γ-herpesviruses.

Abstract

Human herpesvirus infections cover a wide range of pathogenic outcomes and challenging situations in the medical field. All herpesviral α-, β-, and γ-subfamilies comprise representatives with a huge clinical impact on human health. The basic and translational research efforts are strongly directed towards the improved molecular understanding of infections and development of novel antiviral test systems and preventive measures. We utilized cell culture-based quantitative models for the assessment of antiviral prototype drugs against human and animal pathogenic herpesviruses. Our analysis focused on approved, developmental, and experimental compounds. All three investigated herpesviruses showed sensitivity against the selected antivirals. The single-drug antiviral treatments identified mean effective concentrations in the micromolar range, for abemaciclib (ABE) and the pharmacophore compound 020 (P-020), as well as submicromolar to nanomolar range, for brincidofovir (BCV) and cyclin-dependent kinase inhibitor of CDK7 (LDC4297). Time-of-addition experiments addressed questions of temporal potency of inhibition and effects on the expression of individual viral proteins. The results demonstrated that these drugs were mostly robust and did generally show moderate or no difference in antiviral activity when administered pre-, post-, or total duration-infection. By addressing the question of potential drug-drug synergies in combinatorial cotreatment settings, we identified effective conditions of combined antiherpesviral drug treatment (cAHT), such as ABE + LDC4297, as demonstrated for all three viruses. Thus, the study provides new information about antiherpesviral potency and characteristics of a selection of four antiviral prototype inhibitors. Especially, examples of broadness in synergistic combination treatment suggested options to improve antiherpesviral therapy strategies.