The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines

Luban, Jeremy; Sattler, Rachel A.; Mühlberger, Elke; Graci, Jason D.; Cao, Liangxian; Weetall, Marla; Trotta, Christopher R.; Colacino, Joseph M.; Bavari, Sina; Strambio‐De‐Castillia, Caterina; Suder, Ellen L.; Wang, Yetao; Soloveva, Veronica; Cintron-Lue, Katherine; Naryshkin, Nikolai; Pykett, Mark; Welch, Ellen; O’Keefe, Kylie; Kong, Ronald; Goodwin, Elizabeth; Jacobson, Andrew D.; Paessler, Slobodan; Peltz, Stuart W.

doi:10.1016/j.virusres.2020.198246

Cited by 56 publications

(57 citation statements)

References 47 publications

(72 reference statements)

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“…In conclusion, our study while confirming along with others recent reports (12,18) hDHODH as a noteworthy target to inhibit SARS-CoV-2 infection (10,19), highlights MEDS433 as an attractive candidate to develop HTA for COVID-19. MEDS433 in fact performs better than brequinar for both antiviral potency and SI (this study and 16), and its safety profile is superior to that of PTC299 (12). Therefore, the potent in vitro anti-SARS-CoV-2 activity of MEDS433 and its valuable drug-like profile, support further studies to validate its therapeutic efficacy in preclinical animal models of COVID-19.…”

Section: Main Textsupporting

confidence: 91%

“…Given its critical role, hDHODH is considered an emerging target of choice for the development of HTA against SARS-CoV-2 (10). In this regard, two potent hDHODH inhibitors just entered in Phase II clinical trials for COVID-19: brequinar (11) (NCT04425252), and PTC299 (12) (NCT04439071). However, these drug candidates suffer of toxicity issues that slowed down their earlier clinical pathway on other therapeutic applications (13, 14).…”

Section: Main Textmentioning

confidence: 99%

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The new generation hDHODH inhibitor MEDS433 hinders thein vitroreplication of SARS-CoV-2

Calistri¹,

Luganini

Conciatori³

et al. 2020

Preprint

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Identification and development of effective drugs active against SARS-CoV-2 are urgently needed. Here, we report on the anti-SARS-CoV-2 activity of MEDS433, a novel inhibitor of human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidines biosynthesis. MEDS433 inhibits in vitro virus replication in the low nanomolar range, and through a mechanism that stems from its ability to block hDHODH activity. MEDS433 thus represents an attractive candidate to develop novel anti-SARS-CoV-2 agents.

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Section: Main Textsupporting

confidence: 91%

Section: Main Textmentioning

confidence: 99%

The new generation hDHODH inhibitor MEDS433 hinders thein vitroreplication of SARS-CoV-2

Calistri¹,

Luganini

Conciatori³

et al. 2020

Preprint

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show abstract

“…Also, this drug has been found to suppress the release of important cytokines that play a role in ARDS (IL-6, IL17) and vascular endothelial growth factor (VEGF). In addition, a clinical study started on July 9 to investigate the effect of PTC299 on COVID19 (Clinical Code: NCT04439071) [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, new DHODH inhibitors discovered in a number of studies have been demonstrated to suppress both virus infection and cytokine storm [ 33 , 36 , 37 ]. It has been reported that the clinical trials of IMU-838 and PCT299 against COVID19 are ongoing (ClinicalTrials Code: NCT04379271, ClinicalTrials Code: NCT04439071).…”

Section: Introductionmentioning

confidence: 99%

A comprehensive drug repurposing study for COVID19 treatment: novel putative dihydroorotate dehydrogenase inhibitors show association to serotonin–dopamine receptors

Berber

Doluca

2021

Briefings in Bioinformatics

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Dihydroorotate dehydrogenase (DHODH) is a key enzyme required for de novo pyrimidine synthesis and it is suggested as a target for COVID19 treatment due to high pyrimidine demand by the virus replication in the infected host cells as well as its proven effect of blocking of cytokine release by the immune cells to prevent inflammation leading to acute respiratory distress. There are a number of clinical trials underway for COVID19 treatment using DHODH inhibitors; however, there are only a small number of known DHODH antagonists available for testing. Here, we have applied a methodology to identify DHODH antagonist candidates, and compared them using in silico target prediction tools. A large set of 7900 FDA-approved and clinical stage drugs obtained from DrugBank were docked against 20 different structures DHODH available in PDB. Drugs were eliminated according to their predicted affinities by Autodock Vina. About 28 FDA-approved and 79 clinical trial ongoing drugs remained. The mode of interaction of these molecules was analyzed by repeating docking using Autodock 4 and DS Visualiser. Finally, the target region predictions of 28 FDA-approved drugs were determined through PASS and SwissTargetPrediction tools. Interestingly, the analysis of in silico target predictions revealed that serotonin–dopamine receptor antagonists could also be potential DHODH inhibitors. Our candidates shared a common attribute, a possible interaction with serotonin–dopamine receptors as well as other oxidoreductases, like DHODH. Moreover, the Bruton Tyrosine Kinase-inhibitor acalabrutunib and serotonin–dopamine receptor inhibitor drugs on our list have been found in the literature that have shown to be effective against Sars-CoV-2, while the path of activity is yet to be identified. Identifying an effective drug that can suppress both inflammation and virus proliferation will play a crucial role in the treatment of COVID. Therefore, we suggest experimental investigation of the 28 FDA-approved drugs on DHODH activity and Sars-CoV-2 virus proliferation. Those who are found experimentally effective can play an important role in COVID19 treatment. Moreover, we suggest investigating COVID19 case conditions in patients using schizophrenia and depression drugs.

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“…For example, Dihydroorotate dehydrogenase (DHODH) [ 34 ] was considered as drug target for SARS-CoV-2 treatment [ 35 ]. The DHODH Inhibitor ICV617 is a highly potent inhibitor of SARS-CoV-2 replication (EC 50 = 1.96 nM) [ 36 ]. ICV618 can prevent infection by SARS-CoV-2 as an inhibitor of PIKfyve kinase (IC 50 = 10 nM) [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

Ligand-based approach for predicting drug targets and for virtual screening against COVID-19

Yang

Zhu

Wang

et al. 2021

Briefings in Bioinformatics

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Discovering efficient drugs and identifying target proteins are still an unmet but urgent need for curing coronavirus disease 2019 (COVID-19). Protein structure-based docking is a widely applied approach for discovering active compounds against drug targets and for predicting potential targets of active compounds. However, this approach has its inherent deficiency caused by e.g. various different conformations with largely varied binding pockets adopted by proteins, or the lack of true target proteins in the database. This deficiency may result in false negative results. As a complementary approach to the protein structure-based platform for COVID-19, termed as D3Docking in our previous work, we developed in this study a ligand-based method, named D3Similarity, which is based on the molecular similarity evaluation between the submitted molecule(s) and those in an active compound database. The database is constituted by all the reported bioactive molecules against the coronaviruses, viz., severe acute respiratory syndrome coronavirus (SARS), Middle East respiratory syndrome coronavirus (MERS), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human betacoronavirus 2c EMC/2012 (HCoV-EMC), human CoV 229E (HCoV-229E) and feline infectious peritonitis virus (FIPV), some of which have target or mechanism information but some do not. Based on the two-dimensional (2D) and three-dimensional (3D) similarity evaluation of molecular structures, virtual screening and target prediction could be performed according to similarity ranking results. With two examples, we demonstrated the reliability and efficiency of D3Similarity by using 2D × 3D value as score for drug discovery and target prediction against COVID-19. The database, which will be updated regularly, is available free of charge at https://www.d3pharma.com/D3Targets-2019-nCoV/D3Similarity/index.php.

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The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines

Cited by 56 publications

References 47 publications

The new generation hDHODH inhibitor MEDS433 hinders thein vitroreplication of SARS-CoV-2

The new generation hDHODH inhibitor MEDS433 hinders thein vitroreplication of SARS-CoV-2

A comprehensive drug repurposing study for COVID19 treatment: novel putative dihydroorotate dehydrogenase inhibitors show association to serotonin–dopamine receptors

Ligand-based approach for predicting drug targets and for virtual screening against COVID-19

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