A cytopathic retrovirus, human immunodeficiency virus (HIV) has been linked to pathogenesis of the fatal immunosuppressive disease known as Acquired Immune Deficiency Syndrome (AIDS). Replication of the virus is dependent on an RNA-directed DNA polymerase (reverse transcriptase; RT). Other HIV viral gene products that are possible drug targets include an endonuclease (EN) and a protease. In this program it is proposed to develop new compounds that selectively inhibit HIV RT relative to human (alpha, beta, gamma) DNA polymerases, thus providing a potential basis for anti-viral chemotherapy of pre-AIDS patients. Two general classes of such compounds will be synthesized: 1) novel pyrophosphate (PP) analogs; 2) novel hybrid drugs derived from combination of PP inhibitors (1) with nucleoside HIV RT inhibitors (such as AZT, ddT and ddC) into a single nucleotide, 'Masked' derivatives of active inhibitors will be synthesized as potential prodrugs. In addition, 3) nonionic (alkylphosphonate) oligonucleotides with defined sequence will be synthesized as potential HIV EN inhibitors. This approach will be closely linked to group progress on HIV EN enzymology and sequence specification. The new compounds will be carefully characterized with respect to relevant chemical and physical properties. Inhibitors from categories (1) and (2) will be tested for inhibitory activity using purified samples of HIV RT we will also test RT inhibitors for anti-HIV activity in vitro. Structure/function relationships will be determined with respect to absolute HIV RT inhibition and virus/host polymerase inhibition ratios as a function of template and ionic conditions. Determination of acid-base properties, Mg2+ vs. Mn2+ complexation affinities, steric, and other molecular aspects of the inhibitors will be compared with enzymological data on RT to elucidate the role of these factors in HIV RT inhibition. Inhibitors from category (3) will be evaluated in terms of specificity and ID50 value dependence on oligomer length, phosphonate structure, and related factors. The information obtained will be used to evolve rationally designed compounds effective in the treatment of HIV infections.
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