| Autor: |
Calistri A; Department of Molecular Medicine, University of Padua, 35121 Padua, Italy., Luganini A; Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy., Mognetti B; Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy., Elder E; Public Health Agency of Sweden, 17182 Solna, Sweden., Sibille G; Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy., Conciatori V; Department of Molecular Medicine, University of Padua, 35121 Padua, Italy., Del Vecchio C; Department of Molecular Medicine, University of Padua, 35121 Padua, Italy., Sainas S; Department of Sciences and Drug Technology, University of Turin, 10125 Turin, Italy., Boschi D; Department of Sciences and Drug Technology, University of Turin, 10125 Turin, Italy., Montserrat N; Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST), 08028 Barcelona, Spain.; Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain.; Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, 28029 Madrid, Spain., Mirazimi A; Public Health Agency of Sweden, 17182 Solna, Sweden.; Karolinska Institute and Karolinska University Hospital, Department of Laboratory Medicine, Unit of Clinical Microbiology, 17177 Stockholm, Sweden.; National Veterinary Institute, 75189 Uppsala, Sweden., Lolli ML; Department of Sciences and Drug Technology, University of Turin, 10125 Turin, Italy., Gribaudo G; Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy., Parolin C; Department of Molecular Medicine, University of Padua, 35121 Padua, Italy. |
| Abstrakt: |
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 ( h DHODH), 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 h DHODH, the orotate, thus confirming h DHODH 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. |
