On Dihydroorotate Dehydrogenases and Their Inhibitors and Uses

Munier‐Lehmann, Hélène; Vidalain, Pierre‐Olivier; Tangy, Frédéric; Janin, Yves L.

doi:10.1021/jm301848w

Cited by 176 publications

(190 citation statements)

References 251 publications

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“…Brequinar is an inhibitor of dihydroorotate dehydrogenase, the fourth enzyme of pyrimidine biosynthesis pathway, with a potent antiviral activity in vitro 30,31 . When looking at IC50 values, less than one order of magnitude separated this reference molecule from most active hits identified by screening.…”

Section: Representative Resultsmentioning

confidence: 99%

“…Indeed, recent publications suggest that compounds targeting early steps of pyrimidine . In particular, research groups looking for antiviral molecules have found inhibitors of dihydroorotate dehydrogenase, the fourth enzyme of this metabolic pathway 31 . Uridine in culture medium efficiently trans-complements for the inhibition of this enzyme, and thus restores viral replication.…”

Section: Discussionmentioning

confidence: 99%

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High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses

Lucas‐Hourani

Munier‐Lehmann

Helynck

et al. 2014

JoVE

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RNA viruses are responsible for major human diseases such as flu, bronchitis, dengue, Hepatitis C or measles. They also represent an emerging threat because of increased worldwide exchanges and human populations penetrating more and more natural ecosystems. A good example of such an emerging situation is chikungunya virus epidemics of [2005][2006] in the Indian Ocean. Recent progresses in our understanding of cellular pathways controlling viral replication suggest that compounds targeting host cell functions, rather than the virus itself, could inhibit a large panel of RNA viruses. Some broad-spectrum antiviral compounds have been identified with host target-oriented assays. However, measuring the inhibition of viral replication in cell cultures using reduction of cytopathic effects as a readout still represents a paramount screening strategy. Such functional screens have been greatly improved by the development of recombinant viruses expressing reporter enzymes capable of bioluminescence such as luciferase. In the present report, we detail a high-throughput screening pipeline, which combines recombinant measles and chikungunya viruses with cellular viability assays, to identify compounds with a broad-spectrum antiviral profile. Video LinkThe video component of this article can be found at

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Section: Representative Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses

Lucas‐Hourani

Munier‐Lehmann

Helynck

et al. 2014

JoVE

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“…DHODH has been suggested as a target for therapy in multiple diverse disease areas, including oncology, rheumatoid arthritis, multiple sclerosis, and infectious diseases caused by such agents as Plasmodium, bacteria, and viruses (21,29). There are currently two marketed agents that have activity against human DHODH: leflunomide for rheumatoid arthritis and teriflunomide for multiple sclerosis.…”

Section: Discussionmentioning

confidence: 99%

F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase

Oliver¹,

Sibley²,

Beckmann³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

216

268

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There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies. F901318, the leading representative of a novel class of drug, the orotomides, is an antifungal drug in clinical development that demonstrates excellent potency against a broad range of dimorphic and filamentous fungi. In vitro susceptibility testing of F901318 against more than 100 strains from the four main pathogenic Aspergillus spp. revealed minimal inhibitory concentrations of ≤0.06 μg/mLgreater potency than the leading antifungal classes. An investigation into the mechanism of action of F901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Homology modeling of Aspergillus fumigatus DHODH has identified a predicted binding mode of the inhibitor and important interacting amino acid residues. In a murine pulmonary model of aspergillosis, F901318 displays in vivo efficacy against a strain of A. fumigatus sensitive to the azole class of antifungals and a strain displaying an azole-resistant phenotype. F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals.antifungal drug | Aspergillus fumigatus | mechanism of action | dihydroorotate dehydrogenase

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“…The enzyme activity of DHODH has been a highly investigated target for the development of inhibitors used to treat autoimmune diseases and for their use in treatments for cancer and virus and parasitic infections (34). In particular, significant progress has been made in identifying clinically relevant inhibitors of the Plasmodium DHODH that show promise for further clinical development in malaria treatment (10,11).…”

Section: Discussionmentioning

confidence: 99%

Pyrimidine Pathway-Dependent and -Independent Functions of the Toxoplasma gondii Mitochondrial Dihydroorotate Dehydrogenase

et al. 2016

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bDihydroorotate dehydrogenase (DHODH) mediates the fourth step of de novo pyrimidine biosynthesis and is a proven drug target for inducing immunosuppression in therapy of human disease as well as a rapidly emerging drug target for treatment of malaria. In Toxoplasma gondii, disruption of the first, fifth, or sixth step of de novo pyrimidine biosynthesis induced uracil auxotrophy. However, previous attempts to generate uracil auxotrophy by genetically deleting the mitochondrion-associated DHODH of T. gondii (TgDHODH) failed. To further address the essentiality of TgDHODH, mutant gene alleles deficient in TgDHODH activity were designed to ablate the enzyme activity. Replacement of the endogenous DHODH gene with catalytically deficient DHODH gene alleles induced uracil auxotrophy. Catalytically deficient TgDHODH localized to the mitochondria, and parasites retained mitochondrial membrane potential. These results show that TgDHODH is essential for the synthesis of pyrimidines and suggest that TgDHODH is required for a second essential function independent of its role in pyrimidine biosynthesis.

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On Dihydroorotate Dehydrogenases and Their Inhibitors and Uses

Cited by 176 publications

References 251 publications

High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses

High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses

F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase

Pyrimidine Pathway-Dependent and -Independent Functions of the Toxoplasma gondii Mitochondrial Dihydroorotate Dehydrogenase

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