SILK
The project SILK has been chosen to be funded by Regione Piemonte through a highly competitive selection (Regional Grant INFRA P linea B - FSC Azione 173).
The SILK project aims to contribute to the development of novel therapies for COVID-19 and the preparation for future emerging Coronavirus epidemics or pandemics, by leading to clinical trials an innovative pan-Coronavirus Host Targeting Antiviral named MEDS433, a dihydroorotatodehydrogenase (hDHODH ) developed within UniTo. In particular, the necessary research activities will be developed to obtain the proof-of-concept of MEDS433 as a candidate pan-Coronavirus drug with double action in vivo, able to reduce both viral replication and the immunopathogenesis typical of infections by highly pathogenic Coronaviruses such as SARS-CoV-2, and to complete its preclinical path until entry into clinical trials for COVID-19.
The compound, initially designed for the treatment of leukemia, has also been shown to have antiviral properties capable of inhibiting the replication cycle of all coronaviruses. The next steps of the study will have to demonstrate that, the treatment with this compound of cells infected with various coronaviruses, causes not only the blocking of viral replication, but also reducing the inflammatory "cytokine storm" that COVID-19 patients may encounter when the infection with SARS-CoV-2 gets worse. As the compound's antiviral mechanism of action involves host response mechanisms, it is likely that this compound may also be effective against other respiratory viruses that cause severe disease in humans, such as influenza virus and respiratory syncytial virus. (RSV).
On the news
University of Turin press release (link to Italian article)
Fondazione Tempia press release (link to Italian article)
Previous works by our group have lead to this point.
Please have a read at the following abstracts and check the links to the complete articles for details on the background of the SILK project.
The Novel hDHODH Inhibitor MEDS433 Prevents Influenza Virus Replication by Blocking Pyrimidine Biosynthesis
Giulia Sibille, Anna Luganini, Stefano Sainas, Donatella Boschi, Marco Lucio Lolli , Giorgio Gribaudo
The pharmacological management of influenza virus (IV) infections still poses a series of challenges due to the limited anti-IV drug arsenal. Therefore, the development of new anti-influenza agents effective against antigenically different IVs is therefore an urgent priority. To meet this need, host-targeting antivirals (HTAs) can be evaluated as an alternative or complementary approach to current direct-acting agents (DAAs) for the therapy of IV infections. As a contribution to this antiviral strategy, in this study, we characterized the anti-IV activity of MEDS433, a novel small molecule inhibitor of the human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 exhibited a potent antiviral activity against IAV and IBV replication, which was reversed by the addition of exogenous uridine and cytidine or the hDHODH product orotate, thus indicating that MEDS433 targets notably hDHODH activity in IV-infected cells. When MEDS433 was used in combination either with dipyridamole (DPY), an inhibitor of the pyrimidine salvage pathway, or with an anti-IV DAA, such as N4-hydroxycytidine (NHC), synergistic anti-IV activities were observed. As a whole, these results indicate MEDS433 as a potential HTA candidate to develop novel anti-IV intervention approaches, either as a single agent or in combination regimens with DAAs.
Viruses. 2022 Oct 17;14(10):2281. doi: 10.3390/v14102281. Link to article
The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and Other Human Coronaviruses
Arianna Calistri, Anna Luganini, Barbara Mognetti, Elizabeth Elder, Giulia Sibille, Valeria Conciatori, Claudia Del Vecchio, Stefano Sainas, Donatella Boschi, Nuria Montserrat, Ali Mirazimi, Marco Lucio Lolli,
Giorgio Gribaudo, Cristina Parolin
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
Microorganisms 2021, 9(8), 1731; doi: 10.3390/microorganisms9081731. Link to article
Effective deploying of a novel DHODH inhibitor against herpes simplex type 1 and type 2 replication
Anna Luganini, Giulia Sibille, Barbara Mognetti, Stefano Sainas, Agnese Chiara Pippione, Marta Giorgis,
Emergence of drug resistance and adverse effects often affect the efficacy of nucleoside analogues in the therapy of Herpes simplex type 1 (HSV-1) and type 2 (HSV-2) infections. Host-targeting antivirals could therefore be considered as an alternative or complementary strategy in the management of HSV infections. To contribute to this advancement, here we report on the ability of a new generation inhibitor of a key cellular enzyme of de novo pyrimidine biosynthesis, the dihydroorotate dehydrogenase (DHODH), to inhibit HSV-1 and HSV-2 in vitro replication, with a potency comparable to that of the reference drug acyclovir. Analysis of the HSV replication cycle in MEDS433-treated cells revealed that it prevented the accumulation of viral genomes and reduced late gene expression, thus suggesting an impairment at a stage prior to viral DNA replication consistent with the ability of MEDS433 to inhibit DHODH activity. In fact, the anti-HSV activity of MEDS433 was abrogated by the addition of exogenous uridine or of the product of DHODH, the orotate, thus confirming DHODH as the MEDS433 specific target in HSV-infected cells. A combination of MEDS433 with dipyridamole (DPY), an inhibitor of the pyrimidine salvage pathway, was then observed to be effective in inhibiting HSV replication even in the presence of exogenous uridine, thus mimicking in vivo conditions. Finally, when combined with acyclovir and DPY in checkerboard experiments, MEDS433 exhibited highly synergistic antiviral activity. Taken together, these findings suggest that MEDS433 is a promising candidate as either single agent or in combination regimens with existing direct-acting anti-HSV drugs to develop new strategies for treatment of HSV infections.
Antiviral Res. 2021 May; 189:105057. doi: 10.1016/j.antiviral.2021.105057. Link to article
