Effective deploying of a novel DHODH inhibitor against herpes simplex type 1 and type 2 replication

Emergence of drug resistance and adverse effects often affect the efficacy nucleoside analogues in therapy Herpes simplex type 1 (HSV-1) 2 (HSV-2) infections. Host-targeting antivirals could therefore be considered as an alternative or complementary strategy management HSV To contribute to this advancement, here we report on ability a new generation inhibitor key cellular enzyme de novo pyrimidine biosynthesis, dihydroorotate dehydrogenase (DHODH), inhibit HSV-1 HSV-2 vitro replication, with potency comparable that reference acyclovir. Analysis replication cycle MEDS433-treated cells revealed it prevented accumulation viral genomes reduced late gene expression, thus suggesting impairment at stage prior DNA consistent MEDS433 DHODH activity. In fact, anti-HSV activity was abrogated by addition exogenous uridine product DHODH, orotate, confirming specific target HSV-infected cells. A combination dipyridamole (DPY), salvage pathway, then observed effective inhibiting even presence uridine, mimicking vivo conditions. Finally, when combined acyclovir DPY checkerboard experiments, exhibited highly synergistic antiviral Taken together, these findings suggest is promising candidate either single agent regimens existing direct-acting drugs develop strategies for treatment