The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and Other Human Coronaviruses

Abstract

Although coronaviruses (CoVs) have long been predicted to cause zoonotic diseases and pandemics with high probability, the lack of effective anti-pan-CoVs drugs rapidly usable against the emerging SARS-CoV-2 actually prevented a promptly therapeutic intervention for COVID-19. Development of host-targeting antivirals could be an alternative strategy for the control of emerging CoVs infections, as they could be quickly repositioned from one pandemic event to another. To contribute to these pandemic preparedness efforts, here we report on the broad-spectrum CoVs antiviral activity of MEDS433, a new inhibitor of the human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 inhibited the in vitro replication of hCoV-OC43 and hCoV-229E, as well as of SARS-CoV-2, at low nanomolar range. Notably, the anti-SARS-CoV-2 activity of MEDS433 against SARS-CoV-2 was also observed in kidney organoids generated from human embryonic stem cells. Then, the antiviral activity of MEDS433 was reversed by the addition of exogenous uridine or the product of hDHODH, the orotate, thus confirming hDHODH as the specific target of MEDS433 in hCoVs-infected cells. Taken together, these findings suggest MEDS433 as a potential candidate to develop novel drugs for COVID-19, as well as broad-spectrum antiviral agents exploitable for future CoVs threats.

Atovaquone and Berberine Chloride Reduce SARS-CoV-2 Replication In Vitro

“…Of the compounds tested, we found that both atovaquone and brequinar were able to reduce SARS-CoV-2 replication in Vero E6 cells. Both of these molecules are pyrimidine biosynthesis inhibitors and have been shown to inhibit the replication of SARS-CoV-2 and other viruses [13,16,17,[47][48][49][50][51]. These results suggest that pyrimidine biosynthesis is specifically important for SARS-CoV-2 biology since ribavirin, a purine biosynthesis inhibitor, had no impact on SARS-CoV-2 replication.…”

Brequinar and Dipyridamole in Combination Exhibits Synergistic Antiviral Activity Against SARS-CoV-2 in vitro: Rationale for a host-acting antiviral treatment strategy for COVID-19

“…Clinical experience in the oncology space suggests that the impact of available extracellular uridine and the activity of nucleoside transporters may limit the efficacy of DHODHI monotherapy. The in vitro antiviral activity of BRQ alone against SARS-CoV-2 has been reported by others [17, 18, 19]. Given the growing evidence suggesting that DHODH inhibition alone in vitro may not translate to in vivo activity, we explored a host-target antiviral strategy with the combination BRQ and DPY.…”

“…The physiological relevance of 20 µM uridine, some 2-to 9-fold higher than physiologic levels [12], is not clear. been reported by others [17,18,19]. Given the growing evidence suggesting that DHODH inhibition alone in vitro may not translate to in vivo activity, we explored a host-target antiviral strategy with the combination BRQ and DPY.…”

Organoid Studies in COVID-19 Research

“…Similarly, Wysocki and colleagues ( 53 ) used kidney organoids to show that a shorter ACE2 variant had improved neutralizing activity against the infection. A new potential drug candidate, MEDS433, also demonstrated its inhibitory activity on SARS-CoV-2 replication in kidney organoids ( 54 ).…”

“…In addition, Ebisudani and colleagues ( 63 ) have tested the effects of three selected antiviral drugs on lung organoids, identifying remdesivir as the one with the highest activity in preventing SARS-CoV-2 infection. Recent studies have discovered further inhibitors of SARS-CoV-2, including a spike protein inhibitor (EK1 peptide), TMPRSS2 inhibitors (camostat/nafamostat), and a human dihydroorotate dehydrogenase inhibitor (MEDS433) ( 26 , 54 ).…”