Purification by affinity chromatography, subunit structure and inhibition by guanosine 5monophosphate. It has been demonstrated that impdh can aggregate into a macrostructure, termed the cytoophidium, in mammalian cells under a variety of conditions. Vcc234718, a molecule with growth inhibitory activity against mycobacterium tuberculosis mtb, was identified by phenotypic screening of a 15344compound library. Acridonebased compounds have been reported to be potent and uncompetitive inosine monophosphate dehydrogenase impdh inhibitors. Mutations in the inosine monophosphate dehydrogenase 1 gene impdh1 cause the rp10 form of autosomal dominant retinitis pigmentosa. Activesite modification of native and mutant forms of inosine 5monophosphate dehydrogenase from escherichia coli k12. Mycophenolate mofetil is an antimetabolite, antiproliferative drug that acts as an inhibitor of inosine monophosphate dehydrogenase. The major nonimmune effects of mpa are gastrointestinal gi and hematological, which generally respond to dose reductions.
Inosine 5monophosphate dehydrogenase binds nucleic acids in. One such gene is rp10, which encodes human inosine monophosphate dehydrogenase type 1 himpdh1. Conformational stability of hepatitis c virus ns3 protease. Author summary rna viruses have high mutation rates 10. Regulation of the interaction of inosine monophosphate. The cbs subdomain is disordered in many structures, and removal of the. Inosinic acid 5monophosphate dehydrogenase of escherichia coli.
Role of kappa lambda lightchain constantdomain switch in the structure and functionality of a17 reactibody. Inosine monophosphate dehydrogenase how is inosine. In this study, pharmacophore mapping and molecular docking approaches were employed to discover novel homo sapiens impdh himpdh. A transgeneencoded cell surface polypeptide for selection. Identification of antiflaviviral drugs with mosquitocidal. Inosine monophosphate dehydrogenase dependence in a subset of small cell lung cancers author links open overlay panel fang huang 1 2 min ni 2 milind d. Western blot shows lysates of daudi human burkitts lymphoma cell line, raji human burkitts lymphoma cell line, baf3 mouse prob cell line, and nb2.
Ribavirin, an inhibitor of inosine 5monophosphate dehydrogenase impdh, enhances the efficacy of ifnalpha in the treatment of hcv. Jp2012514657a phosphoramidate derivatives of guanosine. However, the regulation and function of the cytoophidium are still elusive. Inosine monophosphate dehydrogenase inhibitors pharmacorama. An orally bioavailable inhibitor of inosine 5 monophosphate dehydrogenase impdh, with potential antineoplastic activity. Inosine monophosphate is oxidised by the enzyme inosine monophosphate dehydrogenase, yielding xanthosine monophosphate, a key precursor in purine metabolism. Though yet to achieve much success in the cancer arena, impdh inhibitors are now widely used in immunosuppressive and antiviral chemotherapy. Impdh has therefore been an attractive target for developing immunosuppressive drugs e. Mrm data were acquired using analyst software version 1. Archives of biochemistry and biophysics april 15, 2008. Top kodi archive and support file vintage software community software apk msdos cdrom software cdrom software library.
Recently, several studies have identified fdaapproved drugs exerting antizikv activity in mammalian cells. A prototypic uncompetitive inhibitor of impdh, mycophenolic acid mpa, is the active form of mycophenolate mofeteil cellcept, a widely used immunosuppressive drug. Inosine 5monophosphate dehydrogenase impdh catalyzes the oxidation of inosine 5monophosphate imp to xanthosine 5monophosphate with the concomitant reduction of nad to nadh. Compare computer program suggested that benzamide riboside, br. It has served as an attractive target in immunosuppressive, anticancer, antiviral, and antiparasitic therapeutic strategies. The hijacking and manipulation of host cell biosynthetic pathways by human viruses are shared molecular events that are essential for the viral life cycle. Retinitis pigmentosa caused by a homozygous mutation in the stargardt disease gene abcr. For those grafts that do survive, most patients have impaired longterm renal function and early allograft loss. Background chemoresistance is the principal reason for poor survival and disease recurrence in osteosarcoma patients. As many as 86 countries and territories have reported evidence of mosquitotransmitted zika infection, and there is no effective means of control. The inosine monophosphate dehydrogenase impdh protein guab2 has been identified as a drugable target in mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into leadlike molecules.
Impdh is a regulator of the intracelluar guanine nucleotide. Deletion of the subdomain decreases affinity 10fold and decreases site size to. This enzyme is found in organisms of all three kingdoms. Intracellularly, mp is converted by hypoxanthine guanine phosphorybosyltransferase into thioinosine monophosphate timp and subsequently into thioguanosine monophosphate by a twostep process involving inosine monophosphate dehydrogenase and guanosine monophosphate synthetase 2. Mycophenolic acid obtained from penicillium culture is an inhibitor of inosine monophosphate dehydrogenase, enzyme responsible of the conversion of inosine monophosphate, imp, into xanthosine monophosphate, xmp, precursor of guanosine derivatives. Sintchak md, fleming ma, futer o, raybuck sa, chambers sp, caron pr, murcko ma, wilson kp 1996 structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Impdh plays a central role in b and t lymphocyte replication. Regulation of inosine monophosphate dehydrogenase type i and type ii isoforms in human lymphocytes.
The presence of peritubular capillary c4d deposition is a. Inosine monophosphate dehydrogenase and transcription. A nucleoside that is involved in purine metabolism, as a precursor and a metabolite of adenosine. It is the ribonucleotide of hypoxanthine and the first nucleotide formed during the synthesis of purine. Fda approved small molecules with activity against the ebola virus.
Coating solution was removed and wells were washed with t cell medium to remove. Here, we have screened such drugs for the ability to reduce. Inosine monophosphate synonyms, inosine monophosphate pronunciation, inosine monophosphate translation, english dictionary definition of inosine monophosphate. There are two isoforms of homo sapiens impdh himpdh. Novel inhibitors of inosine monophosphate dehydrogenase in.
Inosine 5 monophosphate dehydrogenase impdh catalyzes the first unique step of the gmp branch of the purine nucleotide biosynthetic pathway. Found in all forms of life, atp is often referred to as the molecular unit of currency of intracellular energy transfer. Biological roles of cellular glyceraldehyde3phosphate. What is the abbreviation for inosine 5 monophosphate dehydrogenase. Combined human genomewide rnai and metabolite analyses.
Us6479628b1 methods and materials relating to impdh and. It is formed by the deamination of adenosine monophosphate by. Inosine monophosphate dehydrogenase impdh as a target in drug discovery. Herein, we describe the identification of potent impdh inhibitors using fragmentbased screening and. Mammalian ampactivated protein kinase and yeast snf1 protein kinase are the central components of kinase cascades that are highly conserved between animals, fungi, and plants. Retinal isoforms of inosine 5monophosphate dehydrogenase type 1 are poor nucleic acid binding proteins. Impdh abbreviation stands for inosine 5 monophosphate dehydrogenase. Inosine monophosphate dehydrogenase dependence in a subset of. Using a clinically available inhibitor of the purine biosynthetic pathway, they demonstrate reduced growth of ascl1low sclc tumors and favorable combination with chemotherapy in in vivo models. The present invention relates generally to inosine 5. The ampactivated protein kinase cascade acts as a metabolic sensor or fuel gauge that monitors cellular amp and atp levels because it is activated by increases in the amp. However, the zinc ion is not involved in the catalytic mechanism, because it is bound far away from the active site. Mycophenolate mofetil mmf has been utilized to improve gvhd prophylaxis and reduce toxicity. A twelve hour clinical pharmacokinetic and pharmacodynamic study was conducted to study the effects of diabetes on impdh type i and ii gene expression, protein level and enzymatic activity.
Definition of inosine 5 monophosphate dehydrogenase. Xanthinebased acyclic nucleoside phosphonates with potent antiviral activity against varicellazoster virus and human cytomegalovirus show all authors. The present invention contemplates the use of impdh from natural or recombinant sources or sitedirected mutants, and any isoform, sitedirected mutant or a mixture of. Impdh inosine monophosphate dehydrogenase inhibitors. These results highlight the potency of genomescale functional screening for the discovery of drug targets against bacterial infections. Inosine is ribosylhypoxanthine, the base being hypoxanthine, a derivative of adenine. Inosinic acid or inosine monophosphate imp is a nucleoside monophosphate. T cell activation triggers reversible inosine5monophosphate. The present invention relates to an inhibitor of imp dehydrogenase, an inhibitor of viral rna polymerase and a compound of formula i for use in the treatment of an infection caused by a virus from the genus hepevirus in a subject, in particular for use in the treatment of hepatitis e. Ribavirin has been an important component of hepatitis c virus hcv treatment for decades. Impgtp balance modulates cytoophidium assembly and impdh. Defects in the impdh1 gene are a cause of retinitis pigmentosa type 10 rp10.
Recently, a pharmacophore 17 was generated from four fda approved compounds for other diseases nonantivirals resulting from two high throughput screens against the ebola virus 14,15 and closely matched the receptorligand pharmacophores for the ebola viral protein 35 vp35 10. Most inhibitor development programs have focused on himpdh2 since this. Descriptors are arranged in a hierarchical structure, which enables searching at various levels of specificity. Nucleotide sequence of the guab locus encoding imp. Tuberculosis tb remains a major cause of mortality worldwide, and improved treatments are needed to combat emergence of drug resistance.
Adenosine triphosphate atp is an organic compound that provides energy to drive many processes in living cells, e. Proliferation of t and blymphocytes, a hallmark of many autoimnunne diseases. The inosine monophosphate dehydrogenase, guab2, is a. Inosine generally occurs in the first position of the anticodon of certain trna molecules where it can base pair with u, c or a of the codon on mrna. Find out information about inosine monophosphate imp. Coronaviruses lacking exoribonuclease activity are. While rna viruses have long been considered unable to correct mistakes during replication, covs such as sarscov and the recently emerged merscov are important exceptions to this paradigm. Inosine monophosphate dehydrogenase dependence in a subset of small cell lung cancers fang huang,1,2 min ni,2 milind d. A major therpeutic target provides a comphrensive look at the chemotherapeutic inosine monophosphate deydrogenase. In this study, pharmacophore mapping and molecular docking approaches were employed to discover novel homo sapiens impdh himpdh inhibitors. Huffman,4 jiyeon kim,2 ling cai,2,5 xiaolei shi,2 feng cai,2 lauren g. In addition to an overview of the field, this volume examines the molecular biology and gentics, the structure and mechanisms of impdh, inhibitor design, clinical applications, and new trends for the future. Inosine monophosphate harvard catalyst profiles harvard.
Inosine monophosphate dehydrogenase has emerged also as an important. Small molecules with antiviral activity against the. Inosine monophosphate dehydrogenase expression and. Isolation and characterization of mycophenolic acidresistant mutants of inosine5. Impdh1 is an enzyme that catalyzes the synthesis of xanthine monophosphate xmp from inosine 5 monophosphate imp. However, it is also an effective inhibitor of viral rna guanylyl transferase and guanine7n. Disclosed are purified and isolated dna sequences encoding eukaryotic proteins possessing biological properties of inosine 5. Phenotypic screening with a biased targetspecific screen. Wo2011076923a1 inhibitor for inosine monophosphate imp. Impdh inhibitors are in current use and under development as immunosuppressive agents and have potential for the treatment of hematologic malignancies. Inosine monophosphate dehydrogenase as a target for antiviral. Widely used as a flavor enhancer, it is typically obtained from chicken byproducts or other meat industry waste.
Inosine monophosphate is a descriptor in the national library of medicines controlled vocabulary thesaurus, mesh medical subject headings. The initial release 2004 contained 847 human mitochondrial protein sequences, derived from public sequence databases and mass spectrometric analysis of. There are two isoforms of homo sapiens impdh himpdh, labeled types i and ii, which. Inosine monophosphate dehydrogenase dependence in a subset of small cell lung cancers. Inosine monophosphate dehydrogenase dependence in a subset. Although a variety of xenogenic enzymes have been used eg, bacterial neomycin and hygromycin phosphotransferases for in vitro selection of genetically modified cells, these systems suffer from the often prolonged culture necessary to achieve selection, and from the high likelihood that the expressed xenogenic protein will be immunogenic. Hgprt function 4 or cancer uncontrollable activity of inosine5. Inosine monophosphate dehydrogenase as a probe in antiviral. Mitoproteome is an objectrelational mitochondrial geneprotein sequence database and annotation system. Retina contains unique splice variants of impdh1 inosine monophosphate dehydrogenase impdh catalyzes the rate limiting step.
Inosine monophosphate dehydrogenase expression and activity. Author summary zika virus zikv is a human threat with a global health burden. Retinal dystrophies, genomic applications in diagnosis and. Because of increasing evidence of the importance of human glyceraldehyde3phosphate dehydrogenase gapdh in host secretory pathway functions, i hypothesized that this multifunctional enzyme could contribute to life cycles of two. Mutations in this enzyme account for 2% of autosomal dominant rp, however the pathological mechanism is unclear. Inosine monophosphate dehydrogenase type ii is a human, recombinant protein expressed in e. Humanmouserat inosine 5monophosphate dehydrogenase 2. Impd inosine monophosphate dehydrogenase acronymfinder. Xanthinebased acyclic nucleoside phosphonates with potent. It is termed positive if there is extension of the blister andor removal of epidermis in the rubbed area. The presence of donorspecific antihuman leukocyte antigen hla antibodies donorspecific alloantibody before transplantation, and at the time of acute rejection, carries a poor prognosis for renal allograft survival.
Huffman 4 jiyeon kim 2 ling cai 2 5 xiaolei shi 2 feng cai 2 lauren g. Inosine 5monophosphate dehydrogenase impdh is the ratelimiting. The hepatitis c virus ns3 protease is responsible for the processing of the nonstructural region of viral precursor polyprotein in infected hepatic cells. Detection of human, mouse, and rat inosine 5 monophosphate dehydrogenase 2impdh2 by western blot. Antiviral activity of an n allyl acridone against dengue. Impdh is a major target in the design of both antitumor and immunosuppresive drugs. Upon administration, impdh inhibitor ff1050101 competitively inhibits the enzyme impdh, thereby preventing the conversion of inosine monophosphate to xanthosine monophosphate. Mycophenolic acid and thiazole adenine dinucleotide inhibition of tritrichomonas foetus inosine 5. Inosine 5monophosphate dehydrogenase of escherichia coli.
When consumed in metabolic processes, it converts either to adenosine diphosphate. Inosine monophosphate definition of inosine monophosphate. Inosine monophosphate dehydrogenase listed as impd. The most recently published work is at the top of the list. Inosine monophosphate, or inosinic acid, is the ribonucleotide of hypoxanthine and the first nucleotide formed during purine synthesis. Pdf isolation and characterization of mycophenolic acid. Despite the introduction of ribavirin, the current standard treatment of interferon alpha and ribavirin does not excrete the virus in over 50% of patients. Ns3 has been considered a target for drug discovery for a long time. Ribavirin is phosphorylated by cellular adenosine kinase to ribavirin5.
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