SILK
Il progetto SILK è stato scelto per essere finanziato dal bando regionale
INFRA P linea B - FSC Azione 173 (Regione Piemonte).
Il progetto SILK mira a contribuire allo sviluppo di nuove terapie per COVID-19 e alla preparazione per futuri eventi epidemici o pandemici da Coronavirus emergenti, portando fino alla sperimentazione clinica un innovativo Host Targeting Antiviral pan-Coronavirus denominato MEDS433, un inibitore della diidroorotatodeidrogenasi (hDHODH) sviluppato all’interno di UniTo. In particolare, si svilupperanno attività di ricerca necessarie per ottenere il proof-of-concept di MEDS433 come candidato farmaco pan-Coronavirus a doppia azione in vivo, in grado di ridurre sia la replicazione virale, sia l'immunopatogenesi tipica delle infezioni da Coronavirus altamente patogeni come SARS-CoV-2, e di completare il suo percorso preclinico fino all'ingresso nelle sperimentazioni cliniche per COVID-19.
Il composto, inizialmente pensato per le cure della leucemia, ha mostrato di avere una potente attività antivirale in grado di inibire la replicazione di diversi coronavirus umani. I passi successivi dello studio dovranno dimostrare che il trattamento con questo composto delle cellule infettate da vari coronavirus, provoca non solamente il blocco della replicazione virale, ma anche una riduzione della “tempesta citochinica” infiammatoria a cui i pazienti COVID-19 possono andare incontro quando l’infezione con SARS-CoV-2 si aggrava. Poichè il meccanismo d’azione antivirale del composto si basa sulla sua capacità di inibire un enzima dell'ospite, si ritiene che questo composto possa essere efficace anche per altri virus respiratori che causano gravi malattie nell’uomo, come il virus dell’influenza e il virus respiratorio sinciziale (RSV).
On the news
University of Turin press release (link to Italian article)
Fondazione Tempia press release (link to Italian article)
Ricerche precedentemente condotte dal nostro gruppo hanno portato alla proposta del progetto SILK.
L'abstract qui sotto riporta i risultati di questi studi. Utilizzano il link potrete leggere l'intero articolo con tutti i dettagli sulle scoperte scientifiche che hanno portato all'ideazione del progetto SILK.
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
