Abstract
Recent success in defining the human immunodeficiency virus type 1 (HIV-1) – host cell protein interaction network has provided an opportunity for development of novel antiviral therapeutics targeted to host proteins required for virus infection. This expanded earlier successful development of antagonists for the cellular receptors (CD4) and co-receptors (CCR5 or CXCR4) involved in virus attachment. Induction of the G-alphaq signaling cascade by the HIV-1 envelope is required for virus entry, and it’s blocking prevented HIV-1-mediated membrane fusion and initiation of infection. One of the blockers, the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS), was reported to interfere with HIV-1 infection. Since FTS appears to have an established safety record and is being evaluated (as Salirasib, oral) in phase II human clinical trials for treatment of lung cancer, it was of interest to evaluate the potential of FTS as a topical microbicide for prevention of sexual transmission of HIV-1. Data shown here indicated that this compound did not meet the criteria of an established screening algorithm for evaluation of topical microbicides. Nevertheless, the possibility remains to be explored that FTS (especially when used in combination with other anti-HIV drugs) might be useful in sustained pre-exposure prophylaxis to prevent HIV-1 transmission.
Highlights
The global AIDS epidemic has proceeded without abatement for about 30 years with about 36 million people having chronic human immunodeficiency virus type 1 (HIV-1) infections and about 36 million who already succumbed to AIDS
The already ongoing human clinical trials of farnesylthiosalicylic acid (FTS) make this compound an attractive candidate for possible development as a topical microbicide to prevent HIV-1 transmission
MAGI-CCR5 cells, expressing the HIV-1 receptor CD4 and co-receptor CCR5 and beta-galactosidase under the control of the HIV-1 long terminal repeat (LTR), and HIV-1 BaL were obtained from the National Institutes of Health (NIH) AIDS Research and Reference Program (Germantown, MD 20874)
Summary
The global AIDS epidemic has proceeded without abatement for about 30 years with about 36 million people having chronic HIV-1 infections and about 36 million who already succumbed to AIDS. Other prevention strategies are needed, i.e. mechanical or chemical barrier methods The latter correspond to microbicides, topical formulations expected to block HIV-1 infection The already ongoing human clinical trials of FTS (oral Salirasib) make this compound an attractive candidate for possible development as a topical microbicide to prevent HIV-1 transmission. As a first step in this consideration, the inhibitory activity of FTS against infection of cells in vitro was evaluated by a primary assay of a screening algorithm for discovery of topical microbicides (Lackman-Smith et al, 2008). All assays were performed in triplicate and mean values were calculated
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