Pentostatin antagonizes the antiviral activity of MBX-2168 by inhibiting the biosynthesis of the active compound
| Autor: | Terry L. Bowlin, Natalie R. Hagen, Brian G. Gentry, Marie L. Nguyen, John D. Williams |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cyclopropanes Male Guanine viruses 030106 microbiology Foreskin Acyclovir Cytomegalovirus Endogeny Herpesvirus 1 Human Virus Replication Antiviral Agents Article Cell Line 03 medical and health sciences chemistry.chemical_compound Adenosine deaminase Biosynthesis Loss of Function Mutation Polyphosphates Virology Chlorocebus aethiops medicine Pentostatin Animals Humans Phosphorylation Incubation Ganciclovir Vero Cells Pharmacology biology Host Microbial Interactions Chemistry Kinase Herpes Simplex Fibroblasts Molecular biology 030104 developmental biology Mechanism of action Cytomegalovirus Infections Vero cell biology.protein medicine.symptom medicine.drug |
| Zdroj: | Antiviral Res |
| ISSN: | 1872-9096 |
| Popis: | MBX-2168 has a mechanism of action similar to that of acyclovir (ACV) and ganciclovir (GCV), but two unique steps differentiate this drug from ACV/GCV. First, MBX-2168 is, at least partially, phosphorylated by the endogenous cellular kinase TAOK3 to a monophosphate. The second involves the removal of a moiety at the 6-position of MBX-2168-MP by adenosine deaminase like protein-1 (ADAL-1). It has been previously demonstrated that co-incubation with pentostatin (dCF), an ADAL-1 inhibitor, antagonizes the anti-viral activity of MBX-2168. We therefore hypothesize that inhibiting ADAL-1 results in a reduction of active compound produced in virus-infected cells. To test this, we examined the effect dCF has on the conversion of MBX-2168 to a triphosphate in HSV-1 and HCMV-infected cells. Our results demonstrate incubation of MBX-2168 alone or with dCF in HCMV-infected cells resulted in 53.1±0.7 and 39.4±1.5 pmol triphosphate/10(6) cells at 120 hours, respectively. Incubation of MBX-2168 alone or with dCF in Vero cells resulted in 12.8±0.1 and 6.7±0.7 pmol triphosphate/10(6) cells at 24 hours, respectively. HSV-1-infected Vero cells demonstrated no statistical difference in triphosphate accumulation at 24 hours (13.1±0.3 pmol triphosphate/10(6) cells). As expected, incubation with dCF resulted in the accumulation of MBX-2168-MP in both HFF (9.8±0.9 pmol MBX-2168-MP/10(6) cells at 120 hours) and Vero cells (4.7±0.3 pmol MBX-2168-MP/10(6) cells at 24 hours) while no detectable levels of monophosphate were observed in cultures not incubated with dCF. We conclude that dCF antagonizes the anti-viral effect of MBX-2168 by inhibiting the production of triphosphate, the active compound. |
| Databáze: | OpenAIRE |
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