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The Cellular Thioredoxin-1/Thioredoxin Reductase-1 Driven Oxidoreduction Represents a Chemotherapeutic Target for HIV-1 Entry Inhibition
Karolinska Inst, Div Clin Microbiol, Dept Lab Med, F68, Huddinge, Sweden..
Katholieke Univ Leuven, Rega Inst Med Res, Minderbroederstr 10, Leuven, Belgium..
Karolinska Inst, Div Clin Microbiol, Dept Lab Med, F68, Huddinge, Sweden..
Katholieke Univ Leuven, Rega Inst Med Res, Minderbroederstr 10, Leuven, Belgium..
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 1, e0147773Article in journal (Refereed) Published
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Abstract [en]

Background The 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. Results The 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. Conclusion Our findings revealed that thioredoxin-1/thioredoxin reductase-1 acts as a cellular target for the inhibition of HIV entry.

Place, publisher, year, edition, pages
2016. Vol. 11, no 1, e0147773
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Infectious Medicine
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URN: urn:nbn:se:uu:diva-279593DOI: 10.1371/journal.pone.0147773ISI: 000369528200050PubMedID: 26816344OAI: oai:DiVA.org:uu-279593DiVA: diva2:908366
Funder
Swedish Research Council, AK 521-2010-2828Swedish Research Council, LE 621-2011-4006The Karolinska Institutet's Research Foundation
Available from: 2016-03-02 Created: 2016-03-02 Last updated: 2017-11-30Bibliographically approved

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Engman, Lars

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