Abstract
BackgroundCurrent anti-AIDS therapeutic agents and treatment regimens can provide a dramatically improved quality of life for HIV-positive people, many of whom have no detectable viral load for prolonged periods of time. Despite this, curing AIDS remains an elusive goal, partially due to the occurrence of drug resistance. Since the development of resistance is linked to, among other things, fluctuating drug levels, our long-term goal has been to develop nanotechnology-based drug delivery systems that can improve therapy by more precisely controlling drug concentrations in target cells. The theme of the current study is to investigate the value of combining AIDS drugs and modifiers of cellular uptake into macromolecular conjugates having novel pharmacological properties.ResultsBioconjugates were prepared from different combinations of the approved drug, saquinavir, the antiviral agent, R.I.CK-Tat9, the polymeric carrier, poly(ethylene) glycol and the cell uptake enhancer, biotin. Anti-HIV activities were measured in MT-2 cells, an HTLV-1-transformed human lymphoid cell line, infected with HIV-1 strain Vbu 3, while parallel studies were performed in uninfected cells to determine cellular toxicity. For example, R.I.CK-Tat9 was 60 times more potent than L-Tat9 while the addition of biotin resulted in a prodrug that was 2850 times more potent than L-Tat9. Flow cytometry and confocal microscopy studies suggest that variations in intracellular uptake and intracellular localization, as well as synergistic inhibitory effects of SQV and Tat peptides, contributed to the unexpected and substantial differences in antiviral activity.ConclusionOur results demonstrate that highly potent nanoscale multi-drug conjugates with low non-specific toxicity can be produced by combining moieties with anti-HIV agents for different targets onto macromolecules having improved delivery properties.
Highlights
Current anti-Acquired Immunodeficiency Syndrome (AIDS) therapeutic agents and treatment regimens can provide a dramatically improved quality of life for HIV-positive people, many of whom have no detectable viral load for prolonged periods of time
The current results suggest that the increased anti-HIV activity of SQV-PEG3.4 K-R.I.CK-Tat9 is due to the enhanced intracellular uptake and synergistic inhibitory effects of SQV on HIV protease and Tat peptides on both CXCR4 co-receptor interaction and/or human immunodeficiency virus-1 (HIV-1) transcriptional activation
The peptides, L-Tat9, R.I.CKTat9, R.I.CK(biotin)-Tat9, and R.I.CK(ε-carboxyfluorescein)-Tat9 (Figure 2) were synthesized, purified and their structures were confirmed by electrospray ionization mass spectrometry (ESI-MS)
Summary
Current anti-AIDS therapeutic agents and treatment regimens can provide a dramatically improved quality of life for HIV-positive people, many of whom have no detectable viral load for prolonged periods of time. Curing AIDS remains an elusive goal, partially due to the occurrence of drug resistance. Most current anti-Acquired Immunodeficiency Syndrome (AIDS) drugs target two key enzymes in the human immunodeficiency virus-1 (HIV-1) replication cycle, reverse transcriptase and protease. While the remarkable efficacy of protease and reverse transcriptase inhibitor combinations for the treatment of HIV-1 infection has been clearly established in vitro and in the clinic, not even a single AIDS patient has ever been cured. Combination pharmacotherapy remains the most effective strategy for reducing viral loads in HIV-infected patients. Given the variety of new chemical entities under development, combination therapies hold even greater future promise
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