Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers

Abstract

Despite the availability of currently approved antiviral drugs, infections with human cytomegalovirus (HCMV) still cause clinically challenging, sometimes life-threatening situations. There is an urgent need for enhanced anti-HCMV drugs that offer improved efficacy, reduced dosages and options for long-term treatment without risk of the development of viral drug resistance. Recently, we reported the pronounced anti-HCMV efficacy of pharmacological inhibitors of cyclin-dependent kinases (CDKs), in particular, the potential of utilizing drug synergies upon combination treatment with inhibitors of host CDKs and the viral CDK-like kinase pUL97 (vCDK/pUL97). Here, we expand this finding by further assessing the in vitro synergistic antiviral interaction between vCDK and CDK inhibitors towards HCMV as well as non-human cytomegaloviruses. An extension of this synergy approach was achieved in vivo by using the recombinant MCMV-UL97/mouse model, confirming the high potential of combination treatment with the clinically approved vCDK inhibitor maribavir (MBV) and the developmental CDK7 inhibitor LDC4297. Moreover, mechanistic aspects of this synergistic drug combination were illustrated on the levels of intracellular viral protein transport and viral genome replication. The analysis of viral drug resistance did not reveal resistance formation in the case of MBV + LDC4297 combination treatment. Spanning various investigational levels, these new results strongly support our concept, employing the great potential of anti-HCMV synergistic drug treatment.

An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity

“…The Bliss checkerboard data indicated a synergy volume of 163.2 with 95% confidence (µM 2 %), and the Loewe fixed-dose data indicated a weighted combination index of 0.733 (CI wt ). Both results clearly distinguished QRS6 + MBV cotreatment from the areas of additive or antagonistic drug interactions [ 44 , 45 , 74 ] and provided evidence for a statistically significant example of anti-HCMV drug synergism. This finding may have particular importance for future options of vCDK + CDK inhibitors in antiviral combination treatment.…”

Recent Advances on Targeting Proteases for Antiviral Development

“…For example, it is possible to combine viral entry inhibitors and direct acting antivirals to achieve a strong synergistic effect that is on par with current antiviral therapies [ 165 ]. Another possibility is to target similar proteins that are present both in humans and viruses [ 166 ]. This strategy can also come with additional positive effects, like preventing the development of drug-resistant strains, since mutations on a host’s cell proteins usually does not occur, and reduced doses for viral treatment due to higher therapeutical response [ 164 ].…”