In vitro evaluation of current and novel antivirals in combination against human cytomegalovirus
| Autor: | Alexa V. DeVita, Brian G. Gentry, Kylie C. Markovich, Dean Wallace Selleseth, M. Shea O’Brien, Phiroze Sethna |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Cyclopropanes
0301 basic medicine Ganciclovir Foscarnet Human cytomegalovirus Guanine Combination therapy viruses 030106 microbiology Organophosphonates Cytomegalovirus Brincidofovir DNA-Directed DNA Polymerase Pharmacology Virus Replication Antiviral Agents Cell Line Cytosine Viral Proteins 03 medical and health sciences Letermovir chemistry.chemical_compound Virology Drug Resistance Viral medicine Humans Nucleic Acid Synthesis Inhibitors Endodeoxyribonucleases business.industry virus diseases Drug Synergism Maribavir Fibroblasts medicine.disease Drug Combinations chemistry Cytomegalovirus Infections Benzimidazoles Drug Therapy Combination Ribonucleosides business Drug Antagonism Cidofovir medicine.drug |
| Zdroj: | Antiviral Research. 158:255-263 |
| ISSN: | 0166-3542 |
| DOI: | 10.1016/j.antiviral.2018.08.015 |
| Popis: | Human cytomegalovirus (HCMV) can cause severe disease in patients with compromised or immature immune systems. Currently approved pharmacotherapies for the treatment of systemic HCMV infections [ganciclovir (GCV), cidofovir (CDV), foscarnet] are limited by a high incidence of adverse effects and/or the development of drug resistance. Given that many of these drugs have the same viral target (HCMV-encoded DNA polymerase), cross-resistance is relatively common. The primary means to combat drug resistance is combination pharmacotherapy using therapeutics with different molecular mechanisms of action with the expectation that those combinations result in an additive or synergistic enhancement of effect; combinations that result in antagonism can, in many cases, be detrimental to the outcome of the patient. We therefore tested select combinations of approved (GCV, CDV, letermovir (LMV)) and experimental (brincidofovir (BCV), cyclopropavir (CPV), maribavir (MBV), BDCRB) drugs with the hypothesis that combinations of drugs with different and distinct molecular mechanisms of action will produce an additive and/or synergistic enhancement of antiviral effect against HCMV in vitro. Using MacSynergy II (a statistical package that measures enhancement or lessening of effect relative to zero/additive), select drug combination studies demonstrated combination indices ranging from 160 to 372 with 95% confidence intervals greater than zero indicating that these combinations elicit a synergistic enhancement of effect against HCMV in vitro. These data suggest that administration of a viral DNA polymerase inhibitor, MBV, and/or a viral terminase inhibitor in combination has the potential to address the resistance/cross-resistance problems associated with currently available therapeutics. |
| Databáze: | OpenAIRE |
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