Positions

Selected Publications

Academic Article

Year Title Altmetric
2019 Kinetics mechanism and regulation of native human hepatic thymidine phosphorylase 2019
2018 Enzymes of pyrimidine salvage pathways in intraerythrocytic Plasmodium falciparum 2018
2018 Distinct substrate specificity and physicochemical characterization of native human hepatic thymidine phosphorylase 2018
2017 Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets 2017
2015 Kinetic mechanism of Toxoplasma gondii adenosine kinase and the highly efficient utilization of adenosine 2015
2014 Isolation and substrate specificity of an adenine nucleoside phosphorylase from adult Schistosoma mansoni 2014
2014 Nucleoside kinases in adult Schistosoma mansoni: Phosphorylation of pyrimidine nucleosides 2014
2013 Effect of mimetic CDK9 inhibitors on HIV-1-activated transcription 2013
2012 Potent combination therapy for human breast tumors with high doses of 5-fluorouracil: Remission and lack of host toxicity 2012
2010 Paracrine stimulation of endothelial cell motility and angiogenesis by platelet-derived deoxyribose-1-phosphate 2010
2010 Carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase: Biological activities and selective toxicities 2010
2010 Structure-activity relationships of carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase 2010
2008 7-Deaza-6-benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: Activities and selective toxicities 2008
2008 Structure-activity relationships of 7-deaza-6-benzylthioinosine analogues as ligands of Toxoplasma gondii adenosine kinase 2008
2008 Suppression of thymidine phosphorylase expression by promoter methylation in human cancer cells lacking enzyme activity 2008
2008 Uridine protects cortical neurons from glucose deprivation-induced death: Possible role of uridine phosphorylase 2008
2007 Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents 2007
2007 Adenosine metabolism in Toxoplasma gondii: Potential targets for chemotherapy 2007
2007 Editorial: Potential targets for the rational design of antiparasitic drugs 2007
2007 Substrate analogs induce an intermediate conformational change in Toxoplasma gondii adenosine kinase 2007
2006 Modulation of 5-fluorouracil host-toxicity and chemotherapeutic efficacy against human colon tumors by 5-(phenylthio)acyclouridine, a uridine phosphorylase inhibitor 2006
2006 Uridine prevents the glucose deprivation-induced death of immunostimulated astrocytes via the action of uridine phosphorylase. 2006
2006 Structure of Toxoplasma gondii adenosine kinase in complex with an ATP analog at 1.1 Å resolution 2006
2005 6-Benzylthioinosine analogues: Promising anti-toxoplasmic agents as inhibitors of the mammalian nucleoside transporter ENT1 (es) 2005
2005 Structural basis for inhibition of Escherichia coli uridine phosphorylase by 5-substituted acyclouridines 2005
2005 5-(Phenylthio)acyclouridine: A powerful enhancer of oral uridine bioavailability: Relevance to chemotherapy with 5-fluorouracil and other uridine rescue regimens 2005
2005 6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: Activities and selective toxicities 2005
2004 Synthesis, Biological Activity and Molecular Modeling of 6-Benzylthioinosine Analogues as Subversive Substrates of Toxoplasma gondii Adenosine Kinase 2004
2003 Uptake of nitrobenzylthioinosine and purine β-L-nucleosides by intracellular Toxoplasma gondii 2003
2003 Potential chemotherapeutic targets in the purine metabolism of parasites 2003
2002 Trends in the design of nucleoside analogues as anti-HIV drugs 2002
2001 Synthesis of carbocyclic orotidine analogs as potential orotidinedecarboxylase inhibitors 2001
2001 Antiviral activity and intracellular metabolism of bis(tButyISATE) phosphotriester of β-L-2′,3′dideoxyadenosine, a potent inhibitor of HIV and HBV replication 2001
2001 Enhancement of the bioavailability of oral uridine by coadministration of 5-(phenylthio)acyclouridine, a uridine phosphorylase inhibitor: Implications for uridine rescue regimens in chemotherapy 2001
2001 Modulation of the pharmacokinetics of endogenous plasma uridine by 5-(phenylthio)acyclouridine, a uridine phosphorylase inhibitor: Implications for chemotherapy 2001
2000 5-Phenylthioacyclouridine: A potent and specific inhibitor of uridine phosphorylase 2000
2000 Effect of administration of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on the anti-tumor efficacy of 5-fluoro-2'-deoxyuridine against murine colon tumor C26-10 2000
2000 Modulation of 5-fluorouracil host toxicity by 5- (benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2',3',5'-tri-O-acetyluridine, a prodrug of uridine 2000
2000 Intracellular metabolism of β-L-2',3'-dideoxyadenosine: Relevance to its limited antiviral activity 2000
2000 Effect of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on plasma concentration of uridine released from 2', 3', 5'-tri-O-acetyluridine, a prodrug of uridine: Relevance to uridine rescue in chemotherapy 2000
2000 Modulation of plasma uridine concentration by 5- (phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase: Relevance to chemotherapy 2000
1999 The adenosine transporter of Toxoplasma gondii. Identification by insertional mutagenesis, cloning, and recombinant expression 1999
1999 Pyrimidine nucleobase ligands of orotate phosphoribosyltransferase from toxoplasma gondii 1999
1999 Metabolism and selective toxicity of 6-nitrobenzylthioinosine in Toxoplasma gondii 1999
1999 Insertional tagging of at least two loci associated with resistance to adenine arabinoside in Toxoplasma gondii, and cloning of the adenosine kinase locus 1999
1999 Uridine phosphorylase inhibitors: Chemical modification of benzyloxybenzyl-barbituric acid and its effects on UrdPase inhibition 1999
1996 5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2′,3′,5′-tri-O-acetyluridine, a prodrug of uridine, as modulators of plasma uridine concentration: Implications for chemotherapy 1996
1996 Effects of modifications in the pentose moiety and conformational changes on the binding of nucleoside ligands to uridine phosphorylase from Toxoplasma gondii 1996
1995 Structure-activity relationships for the binding of ligands to xanthine or guanine phosphoribosyltransferase from Toxoplasma gondii 1995
1995 Structure-activity relationship for the binding of nucleoside ligands to adenosine kinase from Toxoplasma gondii 1995
1995 Enhancement of 5-Fluoro-2′-deoxyuridine Antitumor Efficacy by the Uridine Phosphorylase Inhibitor 5-(Benzyloxybenzyl)barbituric Acid Acyclonucleoside 1995
1995 Synthesis of [4-(hydroxy)tetrahydrofuran-2-yl]nucleosides as a novel class of uridine phosphorylase inhibitors 1995
1995 Effects of 5-benzylacyclouridine, an inhibitor of uridine phosphorylase, on the pharmacokinetics of uridine in rhesus monkeys: implications for chemotherapy 1995
1994 Potentiation of 5-Fluorouracil Efficacy by the Dihydrouracil Dehydrogenase Inhibitor, 5-Benzyloxybenzyluracil 1994
1993 5-Benzylbarbituric acid derivatives, potent and specific inhibitors of uridine phosphorylase 1993
1993 Circadian rhythm of orotate phosphoribosyltransferase, pyrimidine nucleoside phosphorylases and dihydrouracil dehydrogenase in mouse liver. Possible relevance to chemotherapy with 5-fluoropyrimidines 1993
1993 Differences in Activities and Substrate Specificity of Human and Murine Pyrimidine Nucleoside Phosphorylases: Implications for Chemotherapy with 5-Fluoropyrimidines 1993
1993 Phenylselenenyl- and Phenylthio-Substituted Pyrimidines as Inhibitors of Dihydrouracil Dehydrogenase and Uridine Phosphorylase 1993
1993 Synthesis of a new class of uridine phosphorylase inhibitors 1993
1992 Chemotherapy of schistosomiasis. 1992
1991 Inhibition of fluoropyrimidine catabolism by benzyloxybenzyluracil. Possible relevance to regional chemotherapy 1991
1991 Efficacy of combination therapy with tubercidin and nitrobenzylthioinosine 5'- monophosphate against chronic and advanced stages of schistosomiasis 1991
1990 Circadian rhythm of hepatic uridine phosphorylase activity and plasma concentration of uridine in mice 1990
1990 Pyrimidine salvage pathways in adult Schistosoma mansoni 1990
1989 Structure-activity relationship of ligands of dihydrouracil dehydrogenase from mouse liver 1989
1989 Prevention for tubercidin host toxicity by nitrobenzylthioinosine 5'-monophosphate for the treatment of schistosomiasis 1989
1988 Synthesis of 5-benzyl and 5-benzyloxybenzyl 2,2'-anhydroudridines and related nucleoside analogs as inhibitors of uridine phosphorylase 1988
1988 Effect of the N-glycosidic bond conformation and modifications in the pentose moiety on the binding of nucleoside ligands to uridine phosphorylase 1988
1988 Uridine phosphorylase from Schistosoma mansoni 1988
1987 Treatment of schistosomiasis by purine nucleoside analogues in combination with nucleoside transport inhibitors 1987
1987 New analogues of benzylacyclouridines, specific and potent inhibitors of uridine phosphorylase from human and mouse livers 1987
1987 Metabolism of adenosine analogues by Schistosoma mansoni and the effect of nucleoside transport inhibitors 1987
1987 Effects of N,N-dimethylformamide and sodium butyrate on enzymes of pyrimidine metabolism in cultured human tumor cells 1987
1986 Inhibition of uridine phosphorylase from Escherichia coli by benzylacyclouridines 1986
1985 Combination therapy of Schistosoma japonicum by tubercidin and nitrobenzylthioinosine 5′-monophosphate 1985
1985 Enzymes off Uracil Catabolism in Normal and Neoplastic Human Tissues 1985
1985 Kinetic Studies of Thymidine Phosphorylase from Mouse Liver 1985
1985 Nucleotidase activities of human peripheral lymphocytes 1985
1985 Kinetic studies of thymidine phosphorylase from mouse liver 1985
1985 New inhibitors of dihydrouracil dehydrogenase 1985
1984 Inhibition of Nucleoside Transport in Murine Lymphoma L5178Y Cells and Human Erythrocytes by the Uridine Phosphorylase Inhibitors 5-Benzylacyclouridine and 5-Benzyloxybenzylacyclouridine 1984
1984 Structure-activity relationship of pyrimidine base analogs as ligands of orotate phosphoribosyltransferase 1984
1984 Potentiation of 5-Fluoro-2'-deoxyuridine Antineoplastic Activity by the Uridine Phosphorylase Inhibitors Benzylacyclouridine and Benzyloxybenzylacyclouridine 1984
1984 Enzymes of uridine 5′-monophosphate biosynthesis in Schistosoma mansoni 1984
1984 Synthesis and Biological Activity of Hydroxymethyl Analogs of 5-Benzylacyclouridine and 5-Benzylckybenzyiacyclogridine 1984
1983 Combination therapy of schistosomiasis by tubercidin and nitrobenzylthioinosine 5'-monophosphate. 1983
1983 Structure-activity relationship of ligands of the pyrimidine nucleoside phosphorylases 1983
1983 Combination therapy of schistosomiasis by tubercidin and nitrobenzylthioinosine 5'-monophosphate 1983
1982 5-Benzylacyclouridine and 5-benzyloxybenzylacyclouridine, potent inhibitors of uridine phosphorylase 1982
1982 Isolation and partial characterization of a 5'-nucleotidase specific for orotidine-5'-monophosphate. 1982
1982 Isolation and partial characterization of a 5'-nucleotidase specific for orotidine-5'-monophosphate 1982
1982 New inhibitors of the pyrimidine nucleoside phosphorylases 1982
1981 Pyrimidine acyclonucleosides, inhibitors of uridine phosphorylase 1981
1981 A simple radioisotopic assay for nucleoside kinases employing alumina for separation of nucleosides and nucleotides 1981
1981 Benzyl acyclouridine, a new potent inhibitor of uridine phosphorylase 1981
1981 Isolation of OMPase, A 5'-nucleotidase specific for orotidine-5'-monophosphate 1981
1980 A genetic and dietary study of the physiology of pyrimidine synthesis in Drosophila melanogaster 1980
1980 Acyclopyrimidine nucleosides, a new class of specific inhibitors of uridine phosphorylase 1980
1980 Studies on the utilization of dietary thymidine and thymine by Drosophila melanogaster larvae 1980
1977 Survival of Drosophila melanogaster larvae on defined medium supplemented with naturally occurring nucleosides and nucleic acid bases 1977
1974 Biology of 5-fluoro-2′-deoxyuridine sensitivity of Drosophila melanogaster larvae 1974
1974 Crossbreeding and the effect of certain environmental factors on body weights of Barki and German Merino sheep 1974

Chapter

Year Title Altmetric
2007 Adenosine Metabolism in Toxoplasma gondii: Potential Targets for Chemotherapy.  581-597. 2007
2007 Editorial, Potential Targets for the Rational Design of Antiparasitic Drugs.  553-554. 2007
2003 Potential Chemotherapeutic Targets in the Purine Metabolism of Parasites.  283-309. 2003
2002 Current Trends in Nucleoside Analogues as Anti HIV-Drugs.  581-593. 2002
2002 Purine Metabolism in Parasites: Potential Targets for Chemotherapy.  377-416. 2002
1992 Chemotherapy of Schistosomiasis.  212-216. 1992
1990 Novel Pharmacologic Approaches for the Treatment of AIDS and Potential Use of Uridine Phosphorylase Inhibitors.  63-73. 1990

Research Overview

  • Dr. el Kouni's laboratory is actively participating in wide range of studies, involving pyrimidine and purine metabolism and drug action. His research is in two major areas.

    The first is of studies on a detailed investigation of key enzymes of pyrimidine metabolism, mainly uridine phosphorylase and thymidine phosphorylase. His laboratory was responsible for detailed studies on these two enzymes and the development of a novel class of uridine phosphorylase inhibitors which have potentiative effects with clinically important antitumor (e.g. 5-fluorouracil and 5-fluoro-2'-deoxyuridine) and anti-AIDS (e.g. AZT) agents. He has been awarded 4 patents for the composition and use of these inhibitors. One of these inhibitors is currently in Phase I clinical trials and a second in pre-clinical trials.

    The usefulness of uridine phosphorylase inhibitors designed by Dr. el Kouni's group has been established in the field of experimental chemotherapy of cancer and AIDS by various laboratories including his. These inhibitors were shown to enhance the efficacy of 5-fluoro-2'-deoxyuridine against human tumors in vitro and in vivo. Furthermore, they were shown to elevate the concentration and prolong the half-life of uridine in the plasma, as well as increase the salvage of uridine by various tissues. Therefore, these inhibitors were used to protect against or rescue from host-toxicity of anticancer (i.e. 5-fluorouracil) and anti-HIV (i.e. AZT) drugs, the toxicities of which were shown to be antagonized by administration of exogenous uridine or similar nucleosides.

    In this respect, uridine phosphorylase inhibitors can substitute, totally or partially, for the "uridine rescue regimens" in treating cancer, viral, and other diseases. uridine phosphorylase inhibitors alone or in combination with low concentrations of uridine can maintain adequate uridine concentration for a long enough time to rescue selectively the normal or uninfected cells from drug toxicity, without having to suffer from the toxic side effects (e.g. phlebitis, pyrogenic reactions, changes in body temperature and diarrhea) observed with the high concentration of uridine required to achieve the rescuing or protective effects in the absence of the inhibitor. The use of uridine phosphorylase inhibitors in manipulating uridine pool is not limited to the treatment of cancer or AIDS but can also be extended to treat other pathological and physiological disorders, where administration of uridine has been shown to be useful. Such disorders are quite numerous and include CNS disorders (e.g., cerebrovascular disorders, convulsions, etc.), sleep promotion, muscle performance, liver disease, cardiac damage, etc.

    Dr. el Kouni's laboratory has also established the existence of circadian rhythm in several enzymes of pyrimidine metabolism, including uridine phosphorylase. The circadian rhythm of uridine phosphorylase was the opposite of that of plasma uridine levels and toxicity of 5-fluoro-2'-deoxyuridine. These results emphasize the importance of the time of administration of this important anti-cancer drug.

    The other major area of Dr. el Kouni's research is application of his knowledge of purine and pyrimidine metabolism to the development of new therapeutic approaches for the treatment of schistosomiasis, toxoplasmosis and other parasitic diseases. Schistosomiasis ranks second behind malaria in prevalence as a human disease as it afflicts 200 million people in many parts of the world. Toxoplasmosis is the most commonly recognized of opportunistic infection of the CNS in immunocompromised patients such as those suffering from AIDS. Dr. el Kouni is currently directing a systematic study of purine and pyrimidine metabolism in Toxoplasma gondii with the objective of identifying differences from mammalian metabolism that may be exploited for new chemotherapeutic approaches.
  • Principal Investigator On

    Full Name

  • Mahmoud H. H. el Kouni
  • Fax

  • 205-934-8240