title: The Cellular Thioredoxin-1/Thioredoxin Reductase-1 Driven Oxidoreduction Represents a Chemotherapeutic Target for HIV-1 Entry Inhibition.
abstract: 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.
  
  
  CONCLUSIONS
  Our findings revealed that thioredoxin-1/thioredoxin reductase-1 acts as a cellular target for the inhibition of HIV entry.
authors.affiliation: Karolinska Institute, Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Huddinge, Sweden.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Reiser
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Minderbroederstraat 10, Leuven, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Mathys
authors.affiliation: Karolinska Institute, Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Huddinge, Sweden.
authors.forename: Sophie
authors.initials: S
authors.lastname: Curbo
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Minderbroederstraat 10, Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Minderbroederstraat 10, Leuven, Belgium.
authors.forename: Sam
authors.initials: S
authors.lastname: Noppen
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Minderbroederstraat 10, Leuven, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Liekens
authors.affiliation: Uppsala University, Department of Chemistry-BMC, BOX 576, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Engman
authors.affiliation: Karolinska Institute, Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Huddinge, Sweden.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lundberg
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Minderbroederstraat 10, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Karolinska Institute, Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Huddinge, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D013691:Tellurium / Q000737:chemistry / Q000494:pharmacology*; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D015699:HIV Envelope Protein gp120; D013879:Thioredoxins; D054481:Thioredoxin Reductase 1; D013691:Tellurium
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