Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives (original) (raw)

Nature volume 343, pages 470–474 (1990)Cite this article

Abstract

IN the search for compounds active against human immunodeficiency virus (HIV), we have found that members of a novel series of tetrahydro-imidazo[4,5,1-jk][l,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives inhibit the replication of HIV-1 (refs 1, 2), the main aetiological agent of AIDS, but not of HIV-2 (ref. 3), or of any other DNA or RNA viruses. In five cell systems, HIV-1 is inhibited by TIBO derivatives in nanomolar amounts, which are 104–105 times lower than the cytotoxic concentration. The unprecedented specificity of these compounds may be due to an interaction with a reverse transcriptase-associated process. By contrast, AZT (3′-azido-2′,3′-dideoxythymidine), which is used for the treatment of AIDS, and DDC (2′,3′-dideoxycytidine) and DDI (2′,3′-dideoxyinosine), whose clinical application is being assessed, inhibit both HIV-1 and HIV-2 at concentrations that, depending on the cell systems, are 2 to 4 orders of magnitude below their cytotoxic concentration5–8. TIBO-derivatives are new chemicals unrelated to any other antiviral agents. We believe that they are the most specific and potent inhibitors of HIV-1 replication studied so far.

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Authors and Affiliations

  1. Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium
    Rudi Pauwels, Jan Desmyter, Dominique Schols & Erik De Clercq
  2. Janssen Research Foundation, Turnhoutseweg 30, B-2340, Beerse, Belgium
    Koen Andries, Alfons Raeymaeckers, Jozef Van Gelder, Robert Woestenborghs, Jozef Heykants, Karel Schellekens, Marcel A. C. Janssen & Paul A. J. Janssen
  3. Janssen Research Foundation, Bethlehem Pike, Spring House, Pennsylvania, 19477, USA
    Michael J. Kukla & Henry J. Breslin

Authors

  1. Rudi Pauwels
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  2. Koen Andries
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  3. Jan Desmyter
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  4. Dominique Schols
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  5. Michael J. Kukla
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  6. Henry J. Breslin
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  7. Alfons Raeymaeckers
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  8. Jozef Van Gelder
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  9. Robert Woestenborghs
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  10. Jozef Heykants
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  11. Karel Schellekens
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  12. Marcel A. C. Janssen
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  13. Erik De Clercq
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  14. Paul A. J. Janssen
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Pauwels, R., Andries, K., Desmyter, J. et al. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives.Nature 343, 470–474 (1990). https://doi.org/10.1038/343470a0

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