Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism

Liu, Qi; Gupta, Amita; Okesli-Armlovich, Ayse; Qiao, Wenjie; Fischer, Curt R.; Smith, Mark A.; Carette, Jan E.; Bassik, Michael C.; Khosla, Chaitan

doi:10.1016/j.chembiol.2020.05.002

Cited by 25 publications

(22 citation statements)

References 52 publications

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“…Recent studies have revealed that pyrimidine metabolism participates in SARS‐CoV‐2 infection 32,33 . In the present study, KEGG analysis results demonstrated that pyrimidine metabolism and steroid hormone biosynthesis are the major pathways involved in the host cells after SARS‐CoV‐2 infection.…”

Section: Discussionsupporting

confidence: 52%

Transcriptomic analysis reveals novel mechanisms of SARS‐CoV‐2 infection in human lung cells

Yang

et al. 2020

Immunity Inflam & Disease

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Background Severe acute respiratory syndrome coronavirus clade 2 (SARS‐CoV‐2) is a single‐stranded RNA virus responsible for the global pandemic of the coronavirus disease‐2019 (COVID‐19). To date, there are still no effective approaches for the prevention and treatment of COVID‐19. Objective The present study aims to explore the possible mechanisms of SARS‐CoV‐2 infection in human lung cells. Methods Data interpretation was conducted by recruiting bioinformatics analysis, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways analysis using downloaded data from the NCBI Gene Expression Omnibus database. Results The present study demonstrated that SARS‐CoV‐2 infection induces the upregulation of 14 interferon‐stimulated genes, indicative of immune, and interferon responses to the virus. Notably, genes for pyrimidine metabolism and steroid hormone biosynthesis are selectively enriched in human lung cells after SARS‐CoV‐2 infection, suggesting that altered pyrimidine metabolism and steroid biosynthesis are remarkable, and perhaps druggable features after SARS‐CoV‐2 infection. Besides, there is a strong positive correlation between viral ORF1ab, ORF6, and angiotensin‐converting enzyme 2 (ACE2) expression in human lung cells, implying that ACE2 facilitates SARS‐CoV‐2 infection and replication in host cells probably through the induction of ORF1ab and ORF6.

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Section: Discussionsupporting

confidence: 52%

Transcriptomic analysis reveals novel mechanisms of SARS‐CoV‐2 infection in human lung cells

Yang

et al. 2020

Immunity Inflam & Disease

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“…Liu et al . [ 34 ] showed that suppression of de novo pyrimidine synthesis in antiviral treatment strategies, apart from RNA-dependent RNA polymerase inhibition, may be the target mechanism for many viral pathogens including coronavirus. Indeed, drug targets in the treatment of COVID19 have been determined by a multi-omics study and DHODH has been identified as one of the three target candidates [ 35 ].…”

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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“…While the combination of DPY with inhibitors of de novo pyrimidine biosynthesis has been investigated previously in both in vitro studies and clinical trials to increase the anticancer effects of the latter, the potential of this combination against virus infections has not yet been thoroughly investigated. To this regard, it has been reported very recently the efficacy of a combination of a hDHODH inhibitor, GSK983, with a pyrimidine salvage inhibitor such as the cyclopentenyl uracil (CPU) in suppressing the in vitro replication of dengue virus, even in the presence of physiological concentrations of uridine (Liu et al, 2020). CPU is a uridine analogue able to block the activity of uridine/cytidine kinase 2 (Cysyk et., 1995), a cellular enzyme that phosphorylates uridine to UMP in the pyrimidine ribonucleotide salvage pathway, and therefore acting at a stage downstream from that targeted by DPY (Fitzgerald, 1987).…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

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

Luganini¹,

Sibille²,

Mognetti³

et al. 2021

Antiviral Research

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Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism

Cited by 25 publications

References 52 publications

Transcriptomic analysis reveals novel mechanisms of SARS‐CoV‐2 infection in human lung cells

Transcriptomic analysis reveals novel mechanisms of SARS‐CoV‐2 infection in human lung cells

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

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

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