Synthesis of the inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors

Cholewiński, Grzegorz; Iwaszkiewicz-Grześ, Dorota; Prejs, Michał; Głowacka, Agnieszka; Dzierzbicka, Krystyna

doi:10.3109/14756366.2014.951349

Cited by 21 publications

(9 citation statements)

References 55 publications

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“…Mycophenolic acid inhibits IMPDH, acting analogously to ribavirin to deplete GTP pools. In contrast, brequinar is a compound that acts by inhibiting dihydroorotate dehydrogenase, a key enzyme in pyrimidine synthesis, depleting both CTP and TTP ( 38 , 39 ). By treating cells during viral infection with each compound, we found that the high-fidelity nsP2 variant and double mutant were more resistant to both nucleotide-depleting compounds ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Viral Polymerase-Helicase Complexes Regulate Replication Fidelity To Overcome Intracellular Nucleotide Depletion

Stapleford

Rozen-Gagnon

Das

et al. 2015

J Virol

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To date, the majority of work on RNA virus replication fidelity has focused on the viral RNA polymerase, while the potential role of other viral replicase proteins in this process is poorly understood. Previous studies used resistance to broad-spectrum RNA mutagens, such as ribavirin, to identify polymerases with increased fidelity that avoid misincorporation of such base analogues. We identified a novel variant in the alphavirus viral helicase/protease, nonstructural protein 2 (nsP2) that operates in concert with the viral polymerase nsP4 to further alter replication complex fidelity, a functional linkage that was conserved among the alphavirus genus. Purified chikungunya virus nsP2 presented delayed helicase activity of the high-fidelity enzyme, and yet purified replication complexes manifested stronger RNA polymerization kinetics. Because mutagenic nucleoside analogs such as ribavirin also affect intracellular nucleotide pools, we addressed the link between nucleotide depletion and replication fidelity by using purine and pyrimidine biosynthesis inhibitors. High-fidelity viruses were more resistant to these conditions, and viral growth could be rescued by the addition of exogenous nucleosides, suggesting that mutagenesis by base analogues requires nucleotide pool depletion. This study describes a novel function for nsP2, highlighting the role of other components of the replication complex in regulating viral replication fidelity, and suggests that viruses can alter their replication complex fidelity to overcome intracellular nucleotide-depleting conditions.IMPORTANCE Previous studies using the RNA mutagen ribavirin to select for drug-resistant variants have highlighted the essential role of the viral RNA-dependent RNA polymerase in regulating replication fidelity. However, the role of other viral replicase components in replication fidelity has not been studied in detail. We identified here an RNA mutagen-resistant variant of the nsP2 helicase/protease that conferred increased fidelity and yet could not operate in the same manner as high-fidelity polymerases. We show that the alphavirus helicase is a key component of the fidelity-regulating machinery. Our data show that the RNA mutagenic activity of compounds such as ribavirin is coupled to and potentiated by nucleotide depletion and that RNA viruses can fine-tune their replication fidelity when faced with an intracellular environment depleted of nucleotides.

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Section: Resultsmentioning

confidence: 99%

Viral Polymerase-Helicase Complexes Regulate Replication Fidelity To Overcome Intracellular Nucleotide Depletion

Stapleford

Rozen-Gagnon

Das

et al. 2015

J Virol

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“…MPA 1 is a competitive and reversible inhibitor of inosine-5 0 -monophosphate dehydrogenase (IMPDH), predominantly isoforms II, which is present in tumor cells and in activated lymphocytes [7,8]. MPA 1 is an active substance of immunosuppressive drugs for the prevention of acute and chronic rejection of allogenic organ transplants.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antimicrobial activity of amino acid and peptide derivatives of mycophenolic acid

Siebert

Wysocka

Krawczyk

et al. 2018

European Journal of Medicinal Chemistry

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The series of 16 novel amino acid and peptide mycophenolic acid (MPA) derivatives was obtained as potential antibacterial agents. Coupling of MPA with respective amines was optimized with condensing reagents such as EDCI/DMAP and T3P/TEA. Amino acid analogs were received both as methyl esters and also with the free carboxylic group. The biological activity of the products was tested on five references bacterial strains: Klebsiella pneumoniae ATCC 700603 (ESBL), Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus MRSA ATCC 43300, Staphylococcus aureus MSSA ATCC 25923. Peptide derivatives proved to be the most versatile ones, their MIC values relative to most strains was lower than MPA alone. It has been noted that the activity of amino acid derivatives depends on the configuration at the chiral center in the amino acid unit and methyl esters indicated better antimicrobial activity than analogs with free carboxylic group.

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“…In an attempt to address this issue, significant efforts were focused on bioisosteric replacements along with various structural modifications of 1 to develop potent IMPDH inhibitors, but with limited success 12 , 25 . The MPA has proven to be an effective inducer of differentiation in a number of cancer cell lines (melanoma, leukaemia and prostate cancer).…”

Section: Introductionmentioning

confidence: 99%

Newer human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents

Shah

Kharkar

2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2), being an age-old target, has attracted attention recently for anticancer drug development. Mycophenolic acid (MPA), a well-known immunosuppressant drug, was used a lead structure to design and develop modestly potent and selective analogues. The steep structure–activity relationship (SAR) requirements of the lead molecule left little scope to synthesise newer analogues. Here, newer MPA amides were designed, synthesised and evaluated for hIMPDH2 inhibition and cellular efficacy in breast, prostate and glioblastoma cell lines. Few title compounds exhibited cellular activity profile better than MPA itself. The observed differences in the overall biological profile could be attributed to improved structural and physicochemical properties of the analogues over MPA. This is the first report of the activity of MPA derivatives in glioblastoma, the most aggressive brain cancer.

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Synthesis of the inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors

Cited by 21 publications

References 55 publications

Viral Polymerase-Helicase Complexes Regulate Replication Fidelity To Overcome Intracellular Nucleotide Depletion

Viral Polymerase-Helicase Complexes Regulate Replication Fidelity To Overcome Intracellular Nucleotide Depletion

Synthesis and antimicrobial activity of amino acid and peptide derivatives of mycophenolic acid

Newer human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents

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