| Autor: |
Sibille G; Department of Life Sciences and Systems Biology, University of Torino, 10123 Torino, Italy., Luganini A; Department of Life Sciences and Systems Biology, University of Torino, 10123 Torino, Italy., Sainas S; Department of Sciences and Drug Technology, University of Torino, 10125 Torino, Italy., Boschi D; Department of Sciences and Drug Technology, University of Torino, 10125 Torino, Italy., Lolli ML; Department of Sciences and Drug Technology, University of Torino, 10125 Torino, Italy., Gribaudo G; Department of Life Sciences and Systems Biology, University of Torino, 10123 Torino, Italy. |
| Jazyk: |
angličtina |
| Zdroj: |
Viruses [Viruses] 2022 Oct 17; Vol. 14 (10). Date of Electronic Publication: 2022 Oct 17. |
| DOI: |
10.3390/v14102281 |
| Abstrakt: |
The pharmacological management of influenza virus (IV) infections still poses a series of challenges due to the limited anti-IV drug arsenal. Therefore, the development of new anti-influenza agents effective against antigenically different IVs is therefore an urgent priority. To meet this need, host-targeting antivirals (HTAs) can be evaluated as an alternative or complementary approach to current direct-acting agents (DAAs) for the therapy of IV infections. As a contribution to this antiviral strategy, in this study, we characterized the anti-IV activity of MEDS433, a novel small molecule inhibitor of the human dihydroorotate dehydrogenase ( h DHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 exhibited a potent antiviral activity against IAV and IBV replication, which was reversed by the addition of exogenous uridine and cytidine or the h DHODH product orotate, thus indicating that MEDS433 targets notably h DHODH activity in IV-infected cells. When MEDS433 was used in combination either with dipyridamole (DPY), an inhibitor of the pyrimidine salvage pathway, or with an anti-IV DAA, such as N 4 -hydroxycytidine (NHC), synergistic anti-IV activities were observed. As a whole, these results indicate MEDS433 as a potential HTA candidate to develop novel anti-IV intervention approaches, either as a single agent or in combination regimens with DAAs. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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