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The Novel h DHODH Inhibitor MEDS433 Prevents Influenza Virus Replication by Blocking Pyrimidine Biosynthesis.

Giulia SibilleAnna LuganiniStefano SainasDonatella BoschiMarco Lucio LolliGiorgio Gribaudo
Published in: Viruses (2022)
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.
Keyphrases
  • small molecule
  • randomized controlled trial
  • endothelial cells
  • induced apoptosis
  • signaling pathway
  • cell proliferation
  • cancer therapy
  • risk assessment
  • bone marrow
  • anti inflammatory
  • cell cycle arrest
  • cell therapy