The long range goal of this research is to probe the active site regions of replicative DNA polymerases and to uncover similarities and differences among them by the use of selective, active-site-directed inhibitors. The ability of these and related compounds to stop the growth of cells involved in disease states may be of value in designing drugs for the treatment of cancer and viral infections. The general class of inhibitors that are the subject of this work are N2-substituted 2-aminopurines, their 2'-deoxyribonucleosides and 5'-triphosphates of the latter. Techniques of organic synthesis and structure determination, separation methods, enzymology and cell culture will be employed to achieve the following specific aims: 1) synthesis and testing of deoxyribonucleotide analogs as inhibitors of and substrates for mammalian cell DNA polymerase alpha to explore the structure of the active site of the enzyme; 2) preparation and exploitation of inhibitor-based affinity columns for the purification of DNA polymerase alpha; 3) examination of the mechanism of cytotoxicity of inhibitors toward mammalian cells, and their potential anabolism or catabolism by cellular enzymes; and 4) synthesis and testing of N2-substituted-2'-deoxyguanosine 5'-triphosphates for inhibition of Herpes simplex virus type 1 DNA polymerase, and antiviral activity of suitable base or deoxyribonucleoside derivatives.
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