Antiviral activity of maribavir in combination with other drugs active against human cytomegalovirus

Abstract

The human cytomegalovirus (CMV) UL97 kinase inhibitor maribavir is in Phase III clinical trials as antiviral therapy, including use for infections refractory or resistant to standard therapy. To assess its activity in combination with approved and experimental CMV antivirals, and with the mTor inhibitor rapamycin (sirolimus), drug effects were tested by in vitro checkerboard assays and the data were analyzed using a three dimensional model based on an independent effects definition of additive interactions. Baseline virus and representative drug-resistant mutants were tested. According to the volume of synergy at 95% confidence, maribavir showed additive interactions with foscarnet, cidofovir, letermovir and GW275175X when tested against wild type and mutant viruses, strong antagonism with ganciclovir, and strong synergy with rapamycin, the latter suggesting a potentially useful therapeutic combination.

T-cells immune response controls the high incidence of adenovirus infection in adult allogenic hematopoietic transplantation recipients

“…The use of rapamycin for the GVHD prophylaxis in patients with a reduced intensity conditioning (20% of the patients treated with ATG and 60% of the whole series) may be another explanation for this lack of association. Results not published yet from our laboratory show an anti-HAdV activity of rapamycin, with an IC 50 of 2.3 µM (selective index of 55), as it had been reported for HCMV (12). The lack of association with any demographic data, transplantation or clinical characteristics was independent of the level of HAdV viremia (data not shown).…”

“…Results from our laboratory not yet published show an anti- HAdV activity of rapamycin, with an IC50 of 2.3 mM (selective index of 55), as reported for human cytomegalovirus (HCMV). 12 The lack of association with any demographic data, transplantation or clinical characteristics was independent of the level of HAdV viremia ( data not shown ).…”

Combinatorial Drug Treatments Reveal Promising Anticytomegaloviral Profiles for Clinically Relevant Pharmaceutical Kinase Inhibitors (PKIs)

“…This likewise holds true for many other mechanistically distinct, additive drug combinations, including GCV, which may nevertheless prove beneficial as new HCMV treatments and therefore merit a closer investigation in clinical approaches. As the computer-assisted prediction of a truly synergistic drug combination, however, is almost impossible, an experimental assessment based on the two applied approaches is crucial for ensuring reliability [ 26 , 27 , 65 ]. In the present study, we identified strong synergism between the two PKIs MBV and LDC4297, constituting a very promising experimental outcome of combinatorial assessment.…”

The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting

“…differences in substrate binding, nuclear translocation and drug susceptibility [44,70] [ [71][72][73][74] Similarity and sequence conservation with other kinases low <35% identity with herpesviral kinases, <15% identity with cellular kinases [45,63] [ [48][49][50]75] Sequence conservation ORF-UL97 of HCMVs high no variation of translational start sites, NLS sequences or kinase domains [44] [ 76,77] Related to cell kinases cyclin-dependent kinases (CDKs), viral CDK ortholog functional overlap with CDKs, specific crosstalk with CDK9, CDK7 and CDK1, direct interaction with cyclins [47,55,56,[78][79][80][81][82][83] [57, 84,85] Coregulation of viral replication by pUL97 and cellular kinases several novel cellular kinases, including CDKs, identified to be involved in HCMV replication virus-supporting functions in signaling pathways and nuclear capsid egress [55,56,86,87] [ [88][89][90][91][92][93] Substrate proteins viral, cellular pUL44, pUL69, pp65, Rb, p32/gC1qR, nuclear lamins, EF-1δ, RNAP II, IFI16, SAMHD1 [53,79,87,[94][95][96]…”