Professor of Pharmacology and Toxicology

Senior Scientist, Comprehensive Cancer Center

Senior Scientist, Center for AIDS Research

Member, Pharmaceutical Design Program

Mentor, Academic Internist Training Program

Education:
B.Sc., University of Alexandria, Egypt; M.Sc., University of Alexandria, Egypt; Ph.D., University of Alberta, Canada; M.A. adeundem, Brown University

Research Interests:
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:

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)

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).

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)

Weiming B, Settembre EC, el Kouni MH and Ealick SE.
Aspects of Escherichia coli Uridine Phosphorylase Inhibition by 5-Substituted Acyclouridines. Acta Cyst D61: 863-872 (2005).

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).

Al Safarjalani ON, Rais RH, Shi J, Schinazi RF, Naguib FNM and 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)

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).

el Kouni MH,

Adenosine Metabolism in Toxoplasma gondii: Potential Targets for Chemotherapy Curr Pharm Des 13: 581-597 (2007)

Zhang Y, el Kouni MH,  Ealick, SE.

Substrate Analogs Induced Intermediate Conformational Changes in Toxoplasma gondii Adenosine Kinase

Acta Cryst D63:126-134 (2007).

Kim YA, Sharon A,  Chu CK, Rais RH, Naguib FNM. and  el Kouni MH.  Synthesis, Biological Evaluation, and Molecular Modeling Studies of N⁶-Benzyladenosine Analogues as Anti-Toxoplasma Agents Biochem Pharmacol 73:1558– 1572 (2007)

To contact Dr. el Kouni:
1670 University Boulevard
VH 119A
Birmingham, AL 35294-0019
Phone: (205) 934-1132
Fax: (205) 934-8240
E-mail: melkouni@uab.edu