Session topic

14:30–14:45

Title: Identification of synergistic anticytomegaloviral drug activities using combinations of clinically relevant pharmaceutical kinase inhibitors (PKIs)
ID: O 65
Type: Abstract talk
Talk time: 12 + 3 min
Session: Workshop 11
Antivirals and resistance II

Speaker: Markus Wild (Erlangen/DE)


Abstract - Text

Abstract text (incl. references and figure legends)

Introduction


Human cytomegalovirus (HCMV) is a human pathogenic herpesvirus associated with a variety of clinical symptoms and significant morbidity and mortality in certain risk groups. Current antiviral therapy is impeded by toxicity and drug resistance, urgently calling for improved options based on new drugs and targeting strategies. Host-directed antivirals, including pharmaceutical kinase inhibitors (PKIs), may help to overcome problems of drug resistance, especially when used in combination treatment with approved antivirals.


Objectives


The anti-HCMV efficacy of combinations of preclinical host-directed drugs with approved HCMV antivirals has not been sufficiently assessed to date.


Materials & Methods


We utilized a selection of clinically relevant PKIs with anti-HCMV activity (i.e. cyclin-dependent kinase [CDK] 4/6 inhibitor abemaciclib, CDK7 inhibitor LDC4297 and pUL97 inhibitor maribavir) and assessed the efficacy of PKI-PKI combinations as well as combinations of PKIs with various other anti-HCMV drugs. Two in vitro approaches were employed in parallel to investigate drug interactions, i.e. the Bliss independence checkerboard and the Loewe additivity fixed-dose assays.


Results


Combination of ganciclovir with maribavir exhibited an antagonistic interaction, consistent with the drugs' counteractive antiviral mode of action. Additive efficacy was measured for various combinations of abemaciclib, maribavir and LDC4297, and slightly synergistic interaction for the combinations abemaciclib + LDC4297 and abemaciclib + ganciclovir. A very strong synergism of maribavir + LDC4297 was consistently detected in both approaches and confirmed using varied settings of infection.


Conclusion


This study highlights the potential of preclinical PKIs as new treatment options against HCMV, especially when combined with approved HCMV antivirals. Furthermore, a very strong synergism between maribavir and the host-directed CDK7 inhibitor LDC4297 was identified and confirmed with several varied parameters. This synergism will now be mechanistically elucidated, towards addressing a putative applicability in clinical treatment of HCMV.



Fig. 1: Anti-HCMV drug combinations were assessed using the Bliss independence checkerboard and Loewe additivity fixed-dose assays, identifying a strong synergism between maribavir and CDK7 inhibitor LDC4297.