Abstract
BackgroundThe entry of HIV into its host cell is an interesting target for chemotherapeutic intervention in the life-cycle of the virus. During entry, reduction of disulfide bridges in the viral envelope glycoprotein gp120 by cellular oxidoreductases is crucial. The cellular thioredoxin reductase-1 plays an important role in this oxidoreduction process by recycling electrons to thioredoxin-1. Therefore, thioredoxin reductase-1 inhibitors may inhibit gp120 reduction during HIV-1 entry. In this present study, tellurium-based thioredoxin reductase-1 inhibitors were investigated as potential inhibitors of HIV entry.ResultsThe organotellurium compounds inhibited HIV-1 and HIV-2 replication in cell culture at low micromolar concentrations by targeting an early event in the viral infection cycle. Time-of-drug-addition studies pointed to virus entry as the drug target, more specifically: the organotellurium compound TE-2 showed a profile similar or close to that of the fusion inhibitor enfuvirtide (T-20). Surface plasmon resonance-based interaction studies revealed that the compounds do not directly interact with the HIV envelope glycoproteins gp120 and gp41, nor with soluble CD4, but instead, dose-dependently bind to thioredoxin reductase-1. By inhibiting the thioredoxin-1/thioredoxin reductase-1-directed oxidoreduction of gp120, the organotellurium compounds prevent conformational changes in the viral glycoprotein which are necessary during viral entry.ConclusionOur findings revealed that thioredoxin-1/thioredoxin reductase-1 acts as a cellular target for the inhibition of HIV entry.
Highlights
During the last 30 years, a variety of at least 26 anti-HIV drugs have been approved for clinical use
Time-ofdrug-addition studies pointed to virus entry as the drug target, : the organotellurium compound TE-2 showed a profile similar or close to that of the fusion inhibitor enfuvirtide (T-20)
Surface plasmon resonance-based interaction studies revealed that the compounds do not directly interact with the HIV envelope glycoproteins gp120 and gp41, nor with soluble CD4, but instead, dose-dependently bind to thioredoxin reductase-1
Summary
During the last 30 years, a variety of at least 26 anti-HIV drugs have been approved for clinical use They target the virus at various stages of its life-cycle and can be grouped within the following categories: CCR5 antagonists, fusion inhibitors, nucleoside-, nucleotide- and nonnucleoside reverse transcriptase (RT) inhibitors, integrase inhibitors and protease inhibitors [1]. A combination of drugs that belong to these different categories is currently used for the highly active antiretroviral therapy (HAART), which is capable to cause a nearly complete inhibition of HIV replication. This allows the blood stream to be cleared from virus particles to levels under the detection limit and allows a partial restoration of the immune function [2]. Tellurium-based thioredoxin reductase-1 inhibitors were investigated as potential inhibitors of HIV entry
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