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

Arianna Calistri,Claudia Del Vecchio,Giulia Sibille,Donatella Boschi,Ali Mirazimi,Marco Lucio Lolli,Anna Luganini,Stefano Sainas,Elizabeth Elder,Nuria Montserrat,Valeria Conciatori,Giorgio Gribaudo,Cristina Parolin,Barbara Mognetti

doi:10.3390/microorganisms9081731

Arianna Calistri, Claudia Del Vecchio + Show 12 more

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https://doi.org/10.3390/microorganisms9081731

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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.

Highlights

Even in the best scenario possible, we must not fail to consider that: (1) the evolution of SARS-CoV-2 is leading to virus variants that might escape the antibody-mediated immunity and cause reinfections; (2) the durability of protection afforded by the vaccines is not yet known and it may be limited; (3) the large scale-immunization to achieve a global vaccine coverage may not be complete due to unfolding productive and logistical challenges and reluctance to vaccinate; and (4) the value of the current SARS-CoV-2 specific vaccines for effective prevention of new CoVs that might likely may emerge in future from animal reservoir hosts is unknown [5]
In the last few years, the results of several high-throughput screens to discover broadspectrum antivirals have identified small molecules targeting the host pyrimidine biosynthesis pathway, mostly with the dihydroorotate dehydrogenase (DHODH) activity as their major and specific target [34,35]. These findings highlight the potential of targeting DHODH to design and develop antiviral agents endowed with a high genetic barrier to the development of drug resistance, and the ability to target a broad spectrum of viruses, enabling a therapeutic approach of newly emerging viruses and contributing to preparedness for unforeseen viral threats [36]
We have investigated the anti-CoVs potential of a series of new small molecules already selected as potent inhibitors of human dihydroorotate dehydrogenase (hDHODH) activity

Summary

Introduction

Despite the fact that coronaviruses (CoVs) have long been predicted to cause zoonotic diseases with high probability, as SARS and MERS outbreaks demonstrated, the lack of effective pan-coronavirus (pan-CoVs) antivirals significantly contributed to the vulnerability of our public health systems to the SARS-CoV2 pandemic, making the therapeutic management of COVID-19 mostly supportive, with the only aim to reduce mortality [1,2,3]. Even in the best scenario possible, we must not fail to consider that: (1) the evolution of SARS-CoV-2 is leading to virus variants that might escape the antibody-mediated immunity and cause reinfections; (2) the durability of protection afforded by the vaccines is not yet known and it may be limited; (3) the large scale-immunization to achieve a global vaccine coverage may not be complete due to unfolding productive and logistical challenges and reluctance to vaccinate; and (4) the value of the current SARS-CoV-2 specific vaccines for effective prevention of new CoVs that might likely may emerge in future from animal reservoir hosts is unknown [5]

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