Effective deploying of a novel DHODH inhibitor against herpes simplex type 1 and type 2 replication

Luganini, Anna; Sibille, Giulia; Mognetti, Barbara; Sainas, Stefano; Pippione, Agnese Chiara; Giorgis, Marta; Boschi, Donatella; Lolli, Marco Lucio; Gribaudo, Giorgio

doi:10.1016/j.antiviral.2021.105057

Cited by 25 publications

(21 citation statements)

References 37 publications

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“…While the combination of DPY with inhibitors of de novo pyrimidine biosynthesis has been investigated previously to increase the anticancer effects of the latter compounds [ 46 ], the potential of this combination against virus infections has not yet been thoroughly explored. To this regard, we have recently observed the efficacy of a synergistic combination of MEDS433 with DPY in suppressing the in vitro replication of Herpes simplex virus type 1, even in the presence of hyperphysiological concentration of uridine [ 47 ]. Importantly, the DPY concentrations observed to be effective in combination with MEDS433 were lower than the DPY C max [ 48 ], and therefore clinically achievable in patients treated with DPY.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…In order to determine cell viability, the confluent VERO cells were exposed to increasing concentrations of the peptides (12.5, 25.0, or 50.0 μg mL −1 ), the plate was incubated for 72 h at 37 °C. The number of viable cells was determined using the CellTiter-Glo Luminescent assay (Promega), as described in Luganini et al [ 51 ]. The peptides were assessed for their antiviral activity at a concentration that produced at least 70% cell viability.…”

Section: Methodsmentioning

confidence: 99%

Donkey Milk Fermentation by Lactococcus lactis subsp. cremoris and Lactobacillus rhamnosus Affects the Antiviral and Antibacterial Milk Properties

et al. 2021

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Background: Milk is considered an important source of bioactive peptides, which can be produced by endogenous or starter bacteria, such as lactic acid bacteria, that are considered effective and safe producers of food-grade bioactive peptides. Among the various types of milk, donkey milk has been gaining more and more attention for its nutraceutical properties. Methods: Lactobacillus rhamnosus 17D10 and Lactococcus lactis subsp. cremoris 40FEL3 were selected for their ability to produce peptides from donkey milk. The endogenous peptides and those obtained after bacterial fermentation were assayed for their antioxidant, antibacterial, and antiviral activities. The peptide mixtures were characterized by means of LC-MS/MS and then analyzed in silico using the Milk Bioactive Peptide DataBase. Results: The peptides produced by the two selected bacteria enhanced the antioxidant activity and reduced E. coli growth. Only the peptides produced by L. rhamnosus 17D10 were able to reduce S. aureus growth. All the peptide mixtures were able to inhibit the replication of HSV-1 by more than 50%. Seventeen peptides were found to have 60% sequence similarity with already known bioactive peptides. Conclusions: A lactic acid bacterium fermentation process is able to enhance the value of donkey milk through bioactivities that are important for human health.

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“…Calistri et al demonstrated that MEDS433 inhibited in vitro replication of HCoV-OC43 (EC 50 = 0.012 μM), HCoV-229E (EC 50 = 0.022 μM), and SARS-CoV-2 (EC 50 = 0.063 μM in Vero E6, EC 50 = 0.076 μM in Calu-3) at nanomolar range with low toxicity [ 90 ]. Luganinia et al demonstrated that MEDS433 inhibited herpes simplex virus-1 and -2 in vitro (EC 50 ~0.1 μM) and exhibited highly synergistic antiviral activity when combined with acyclovir (a DAA) in a checkerboard assay [ 91 ].…”

Section: Dhodhi Applications In Antiviral Treatmentmentioning

confidence: 99%

A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses

Song

et al. 2022

Viruses

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New strategies to rapidly develop broad-spectrum antiviral therapies are urgently required for emerging and re-emerging viruses. Host-targeting antivirals (HTAs) that target the universal host factors necessary for viral replication are the most promising approach, with broad-spectrum, foresighted function, and low resistance. We and others recently identified that host dihydroorotate dehydrogenase (DHODH) is one of the universal host factors essential for the replication of many acute-infectious viruses. DHODH is a rate-limiting enzyme catalyzing the fourth step in de novo pyrimidine synthesis. Therefore, it has also been developed as a therapeutic target for many diseases relying on cellular pyrimidine resources, such as cancers, autoimmune diseases, and viral or bacterial infections. Significantly, the successful use of DHODH inhibitors (DHODHi) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection further supports the application prospects. This review focuses on the advantages of HTAs and the antiviral effects of DHODHi with clinical applications. The multiple functions of DHODHi in inhibiting viral replication, stimulating ISGs expression, and suppressing cytokine storms make DHODHi a potent strategy against viral infection.

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Effective deploying of a novel DHODH inhibitor against herpes simplex type 1 and type 2 replication

Cited by 25 publications

References 37 publications

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

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

Donkey Milk Fermentation by Lactococcus lactis subsp. cremoris and Lactobacillus rhamnosus Affects the Antiviral and Antibacterial Milk Properties

A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses

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