The tat gene of human immunodeficiency virus type 1 (HIV-l), essential for viral replication, is involved in transactivation of HIV-1 LTR-directed gene expression. To date, the molecular mechanisms by which the Tat protein interacts with the HIV-1 LTR appears to be unique to HIV-1 and some closely related lentiviruses. The long term goal of the research in this proposal is to understand the mechanism of action of Tat and, therefore, contribute to the rational design of methods for interfering with Tat function.
The specific aims of this proposal are: 1. To express wild type and mutant Tat proteins in cell-free systems and investigate structural features important for activity. 2. To express wild type and mutant Tat proteins from an adenovirus vector and identify cellular proteins that bind to Tat during the process of transactivation. 3. To construct mutant HIV-2 Tat proteins and chimeras between HIV-1 and HIV-2 Tat proteins and analyze similarities, as well as differences, between these related, but biologically disstinct, proteins. We will use the knowledge obtained from experiments dealing with these specific aims to attempt to devise methods of blockdng Tat activity and, therefore, HIV-1 replication in tissue culture. Practical synthetic approaches to several new """"""""purine-like"""""""" C-Nucleosides are described. These substances are structurally related to several new purine nucleoside antimetabolites synthesized recently in our laboratory, among others, the 9-deazapurine C-nucleosides and their thieno[3,2-d] and furo[3,2-d] pyrimidine congeners which have exhibited a wide spectrum of useful biological activity. The rationales offered are based on: a) the demonstrated anticancer, anti- trypanosomal and antileishmanial activity of several members of the 9-deazapurine C-nucleosides and their thieno and furo congeners and b) their potential use as biochemical probes as specific inhibitors of key purine metabolism enzymes. It is suggested that the candidates may possess chemotherapeutic properties similar to those of the lead compounds. Biological studies for the proper antitumor evaluations of all target C- nucleosides are described. Other collaborative studies would help evaluate their antiprotozoal properties and inhibitory activities against Purine Nucleoside Phosphorylase and Methylthio Adenosine Phosphorylase. Relationships between chemical structures and biological activity should be ascertainable from these investigations.
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