Adenosine Kinase Target for Chemotherapy in T. gondii

<P>
One feature of the metabolic pathway of T. gondii which distinguishes it form its human host is its inability to synthesize purine nucleotides de novo. Therefore, these organisms rely on the purine salvage pathways for their supply of purine nucleotides. </p>
<P>
There are unique features of purine metabolism in T. gondii which render the purine salvage pathways suitable targets for chemotherapy. T. gondii, unlike their mammalian hosts, predominantly salvage their purine precursors via adenosine kinase. On the basis of Dr. el Kouni's detailed structure-activity relationship studies on T. gondii adenosine kinase activity, he has identified a group of compounds, the 6-substituted 9-beta-D-ribofuranosylpurines, as potentially good substrates for this enzyme.</P>
<P>
One of these compounds, NBMPR, is phosphorylated by the parasite adenosine kinase and are also toxic against T. gondii. Furthermore, in collaboration with Dr. David Roos, the T. gondii adenosine kinase gene was successfully cloned to provide a potentially stable source of this enzyme for further studies. </p>
<P>
The overall goal of these studies is to exploit the differences between host and parasite adenosine kinases for the development of chemotherapeutic agents against toxoplasmosis. </p>
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There are three specific aims in this proposal:
<ol>
<li> Overexpress a construct o the recently cloned T. gondii adenosine kinase gene to provide a stable source of this enzyme and to purify and characterize the cloned enzyme for drug screening and design; </li>
<li> determine the mechanism of selective toxicity of the 6-substituted-9-beta-D ribofuranosylpurines in T. gondii;</li>
<li> evaluate active compounds as potential antitoxoplasmosis agents in vitro and in vivo.</li></ol></p>