Effective therapeutics which can inhibit the replication of SARS-CoV-2 in infected individuals are still under development. Several studies suggested the use of drug combinations which can inhibit or prevent SARS-CoV-2 infection. Weeks before, we wrote an article on the study which showed that, the use of combination of Pegasys (IFNa) and nafamostat can effectively prevent SARS-CoV-2 infection in cell culture and hamsters. Now, Dr. Kim Stegmann and colleagues showed that the combination of NHC and DHODH inhibitors such as teriflunomide, IMU-838/vidofludimus, and BAY2402234, strongly synergizes to inhibit SARS-CoV-2 replication. Their study recently appeared in BioRxiv.
The nucleoside analogue N4-hydroxycytidine (NHC), also known as EIDD-1931, interferes with SARS-CoV-2 replication in cell culture. It is the active metabolite of the prodrug Molnupiravir (MK-4482), which is currently being evaluated for the treatment of COVID-19 in advanced clinical studies. Meanwhile, inhibitors of dihydroorotate dehydrogenase (DHODH), by reducing the cellular synthesis of pyrimidines, counteract virus replication and are also being clinically evaluated for COVID-19 therapy.
Now, Kim Stegmann and colleagues carried out study to determine the effectiveness of single and combination of NHC and DHODH inhibitors, in preventing SARS-CoV-2 infection.
They showed that the combination of NHC and DHODH inhibitors such as teriflunomide, IMU-838/vidofludimus, and BAY2402234, strongly synergizes to inhibit SARS-CoV-2 replication. While single drug treatment only mildly impaired virus replication, combination treatments reduced virus yields by at least two orders of magnitude.
They determined this by RT-PCR, TCID50, immunoblot and immunofluorescence assays in Vero E6 and Calu-3 cells infected with wildtype and the Alpha and Beta variants of SARS-CoV-2.
They proposed that the lack of available pyrimidine nucleotides upon DHODH inhibition increases the incorporation of NHC in nascent viral RNA, thus precluding the correct synthesis of the viral genome in subsequent rounds of replication, thereby inhibiting the production of replication competent virus particles. This concept was further supported by the rescue of replicating virus after addition of pyrimidine nucleosides to the media.
“Since both classes of compounds are undergoing advanced clinical evaluation for the treatment of COVID-19, our observations at least raise the prespective of using both drugs as antiviral combination therapy.”— concluded authors of the study
Reference: Kim M. Stegmann, Antje Dickmanns, Natalie Heinen, Uwe Groß, Dirk Görlich, Stephanie Pfaender, Matthias Dobbelstein, “N4-hydroxycytidine and inhibitors of dihydroorotate dehydrogenase synergistically suppress SARS-CoV-2 replication”, bioRxiv 2021.06.28.450163; doi: https://doi.org/10.1101/2021.06.28.450163
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