Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/184453
Title: The new generation hdhodh inhibitor meds433 hinders the in vitro replication of sars-cov-2 and other human coronaviruses
Author: Calistri, Arianna
Montserrat Pulido, Núria
Mirazimi, Ali
Lolli, Marco Lucio
Parolin, Cristina
Luganini, Anna
Mognetti, Barbara
Elder, Elizabeth
Sibille, Giulia
Conciatori, Valeria
Vecchio, Claudia del
Sainas, Stefano
Boschi, Donatella
Keywords: Betacoronavirus
Antiretrovirals
Betacoronavirus
Antiretroviral agents
Issue Date: 1-Aug-2021
Publisher: MDPI AG
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 in-hibited 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.
Note: Reproducció del document publicat a: https://doi.org/10.3390/microorganisms9081731
It is part of: Microorganisms, 2021, vol 9, num 8
URI: http://hdl.handle.net/2445/184453
Related resource: https://doi.org/10.3390/microorganisms9081731
ISSN: 2076-2607
Appears in Collections:Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))
Publicacions de projectes de recerca finançats per la UE

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