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Faculty Detail    
Name MAHMOUD H EL KOUNI
B.Sc.Hon., M.A., M.Sc., Ph.D.
 
Campus Address VH 255 Zip 0019
Phone  (20-5) -132
E-mail  melkouni@uab.edu
Other websites
     


Faculty Appointment(s)
Appointment Type Department Division Rank
Primary  Pharmacology/Toxicology   Pharmacology/Toxicology Chair's Office Professor

Graduate Biomedical Sciences Affiliations
Integrative Biomedical Sciences 
Medical Scientist Training Program 

Society Memberships
Organization Name Position Held Org Link
American Association for Pharmacology and Experimental Therapeuti  member    
American Association for the Advancement of Science  member    
American Association of Cancer Research  member   
American Society of Biochemistry and Molecular Biology  member    
American Society of Tropical Medicine and Hygiene  member   
International Society for Nucleosides, Nucleotides and Nucleic Acids  member    



Research/Clinical Interest
Title
Pyrimidine and purine metabolism, drug design and development
Description
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. It is to his credit that 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 already 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. The potential use of BBBA and other uridine phosphorylase inhibitors in treating such disorders has not yet been recognized in contemporary experimental or applied chemotherapy. 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. Already he has made the important discovery of substantial differences in the metabolism of 6-substituted purine nucleosides in toxoplasma as compared to mammals. Toxoplasma metabolize these compounds to previously unknown toxic intermediates while mammalian systems do not. Administration of such compounds double the life span of animals infected with toxoplasma. A patent for the use of these compounds is currently pending.

Selected Publications 
Publication PUBMEDID
OH T, el Kouni MH.Distinct Substrate Specificity and Physicochemical Characterization of Native Human Hepatic Thymidine Phosphorylase. PLoS ONE 13: e0202826. (2018)   30138393  
el Kouni MH. Pyrimidine Metabolism in Schistosomes: A comparison with Other Parasites and the Search for Potential Chemotherapeutic Targets. Comp Biochem Physiol Part B 213: 55–80 (2017)   28735972  
Naguib FN, Rais RH, Al Safarjalani ON, el Kouni MH. Kinetic mechanism of Toxoplasma gondii adenosine kinase and the highly efficient utilization of adenosine. Comp Biochem Physiol B Biochem Mol Biol 188:63-69 (2015)   26112826 
Naguib FNM and el Kouni MH. Nucleoside Kinases in Adult Schistosoma mansoni: Phosphorylation of Pyrimidine Nucleosides. Mol Biochem Parasitol 194: 53-55 (2014)  24786512 
Savarese TM, el Kouni MH. Isolation and Substrate Specificity of an Adenine Nucleoside Phosphorylase from Adult Schistosoma mansoni Mol Biochem Parasitol 194: 44-47 (2014)   24794680 
Van Duyne R, Guendel I, Jaworski E, Sampey G, Klase Z, Chen H, Zeng C, Kovalskyy D, el Kouni MH, Lepene B, Patanarut A, Nekhai S, Price DH, Kashanchi F. Effect of Mimetic CDK9 Inhibitors on HIV-1-Activated Transcription. J Molec Biol 425:812-29 (2013)  23247501 
Al Safarjalani ON, Rais R, Naguib FNM and el Kouni MH. Potent Combination Therapy for Human Breast Tumors with High Doses of 5-Fluorouracil: Remission and Lack of Host-Toxicity.Cancer Chemother Pharmacol 69:1449–1455 (2012)  22373605 
Al Safarjalani ON, Rais RH, Kim YA, Chu CK, Naguib FN, el Kouni MH. Carbocyclic 6-benzylthioinosine Analogues as Subversive Substrate of Toxoplasma gondii Adenosine Kinase: Biological Activities and Selective Toxicities. Biochem Pharmacol 80:955-963 (2010)   20541538 
Pulaa, WB, Dunn E. Garonnaa K, Watsona E, Hiranoc M, Pizzorno G, Schwartze EL, el Kouni MH,Wheeler-Jones CPD. Paracrine Stimulation of Endothelial Cell Motility and Angiogenesis by Platelet-derived Deoxyribose-1-phosphate. J Arteriosclerosis, Thrombosis, Vascular12:2631-2638 (2010)  20884872 
Kim YA, Rawal RK, Yoo J, Sharon A, Jha AK, Chu CK, Rais RH, Al Safarjalani ON, Naguib FN,el Kouni MH.Structure-activity relationships of carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase. Bioorg Med Chem. 18:3403-3412.(2010)   20456959 
Choi JW, Shin CY, Choi MS, Yoon SY, Ryu JH, Lee JC, Kim WK, el Kouni MH, Ko KH. Uridine protects cortical neurons from glucose deprivation-induced death: Possible role of uridine phosphorylase. J Neurotrauma. 25:695–707 (2008)  18457515 
Guarcello V, Blanquicett C, Naguib FN, el Kouni MH..Suppression of thymidine phosphorylase expression by promoter methylation in human cancer cells lacking enzyme activity. Cancer Chemother Pharmacol 62:85-96 (2008)   17805539 
Zhang Y, el Kouni MH, Ealick SE.Substrate analogs induce an intermediate conformational change in Toxoplasma gondii adenosine kinase. Acta Crystallogr D Biol Crystallogr 63(Pt 2):126-34 (2007)   17242506 
el Kouni MH. Adenosine Metabolism in Toxoplasma gondii: Potential Targets for Chemotherapy. Curr Pharm Des 13: 581-597 (2007)  17346176 
Kim YA, Sharon A, Chu CK, Rais RH, Al Safarjalani ON, Naguib FN, el Kouni MH.Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents.Biochem Pharmacol 73:1558-72(2007)  17306769  
Al Safarjalani ON, Rais R, Shi J, Schinazi RF, Naguib FN, el Kouni MH, Modulation of 5-fluorouracil host-toxicity and chemotherapeutic efficacy against human colon tumors by 5-(Phenylthio)acyclouridine, a uridine phosphorylase inhibitor. Cancer Chemother Pharmacol 58:692-698 (2006)   6528530  
Zhang Y, el Kouni MH , Ealick SE.Crystal structure of Toxoplasma gondii adenosine kinase in complex with an ATP analog at 1.1 Å resolution. Acta Cyst D61: 140-145 (2006)  16421444 
Al Safarjalani ON, Zhou, X-J, Rais RH, Shi J, Schinazi RF, Naguib FNM and el Kouni MH. 5-(Phenylthio)acyclouridine, a powerful enhancer of oral uridine bioavailability: Relevance to chemotherapy with 5-fluorouracil and other uridine rescue regimens. Cancer Chemother Pharmacol 55:541-551 (2005)  5729584 
Weiming B, Settembre EC, el Kouni MH and Ealick SE. Aspects of Escherichia coli uridine phosphorylase inhibition by 5-substituted acyclouridines. Acta Cystalograph D 61:863-72(2005)  5983408 
Al Safarjalani ON, Zhou X-J, Rais RH, Shi J, Schinazi RF, Naguib FNM and el Kouni MH.5-(Phenylthio)acyclouridine, a Powerful Enhancer of Oral Uridine Bioavailability: Relevance to Chemotherapy with 5-fluorouracil and Other Uridine Rescue Regimens. Cancer Chemother. Pharmacol. 55: 541-551 (2005).
 
15729584  
Rais RH, Al Safarjalani ON, Yadav V, Guarcello V, Kirk M, Chu CK, Naguib FNM, and el Kouni MH. 6-Benzylthioinosine Analogues as Subversive Substrate of Toxoplasma gondii Adenosine Kinase: Activities and Selective Toxicities. Biochem Pharmacol 69: 1409-1419 (2005)  15857605  
Gupte A, Buolamwini JK,Yadav V, Chu CK, Naguib FNM and el Kouni MH.6-Benzylthioinosine Analogues Promising Antitoxoplasmic Agents as Inhibitors of the Mammalian Nucleoside Transporter ENT1 (es). Biochem Pharmacol 71:69-73(2005)  16310172 
el Kouni MH. Potential Chemotherapeutic Targets in the Purine Metabolism of Parasites. Pharmac Therapt 99: 283-309 (2003)  12951162  
Yadav V, Chu C K, Rais RH, Al Safarjalani ON, Guarcello V, Naguib FNM and el Kouni MH. Synthesis, Biological Activity and Molecular Modeling of 6-Benzylthioinosine Analogues as Subversive Substrates of Toxoplasma gondii Adenosine Kinase. J Med Chem 47: 1987-1996 (2004)   15055998 
Al Safarjalani ON, Naguib, FNM and el Kouni MH. Uptake of Nitrobenzylthioinosine and Purine â-L-Nucleosides by Intracellular Toxoplasma gondii. Antiviral Chem. Chemother 47:32347-3251(2003)  15055998  
el Kouni MH.Trends in the design of nucleoside analogues as anti-HIV drugs. Curr Pharm Des 8:581-93 (2002)  11945160  

Keywords
Drug design & development, nucleotide metabolism, Cancer, parasites, viral