The specific objectives of the studies of antiviral selectivity proposed in the contract are: 1. To determine the degree of antiviral selectivity of compounds in human peripheral blood mononuclear cells, in a T cell line (MT2), and in human macrophages. (2) To determine in cell culture if a combined chemotherapeutic approach can be additive or synergistic without increased toxicity. (3) To determine if the selected drugs or combinations are effective in inhibiting AZT-resistant HIV-1. (4) To determine the intracellular levels of the combined drugs (and potential metabolites) in primary human lymphocytes compared to those individual drugs under similar conditions. (5) To determine the biochemical basis for additive or synergistic interactions of the combinations. Additional studies described in the proposal include the following: (1) To determine the intracellular levels of combined drugs (and potential metabolites) in human lymphocytes when drug a is withdrawn at different times after pulsing with radiolabeled compound. (2) To evaluate compounds that are selective against human and non-human retrovirus reverse transcriptases (RTs) to determine if they are specific for HIV-1 RT. (3) To determine the inhibition constant (Ki) and mechanism of inhibition (e.g., competitive, etc.) for the compounds that are selective against the purified enzyme. (4) To determine the type of interaction produced between the new compounds identified as selective anti-HIV-1 RT inhibitors when combined at different ratios with other known anti-HIV-1 compounds. (5) To determine whether the compounds or combination can interfere in the binding of gp120 to CD4.
|Schinazi, R F; Chu, C K; Peck, A et al. (1992) Activities of the four optical isomers of 2',3'-dideoxy-3'-thiacytidine (BCH-189) against human immunodeficiency virus type 1 in human lymphocytes. Antimicrob Agents Chemother 36:672-6|