High potency of indolyl aryl sulfone nonnucleoside inhibitors towards drug-resistant human immunodeficiency virus type 1 reverse transcriptase mutants is due to selective targeting of different mechanistic forms of the enzyme.

نویسندگان

  • Reynel Cancio
  • Romano Silvestri
  • Rino Ragno
  • Marino Artico
  • Gabriella De Martino
  • Giuseppe La Regina
  • Emmanuele Crespan
  • Samantha Zanoli
  • Ulrich Hübscher
  • Silvio Spadari
  • Giovanni Maga
چکیده

Indolyl aryl sulfone (IAS) nonnucleoside inhibitors have been shown to potently inhibit the growth of wild-type and drug-resistant human immunodeficiency virus type 1 (HIV-1), but their exact mechanism of action has not been elucidated yet. Here, we describe the mechanism of inhibition of HIV-1 reverse transcriptase (RT) by selected IAS derivatives. Our results showed that, depending on the substitutions introduced in the IAS common pharmacophore, these compounds can be made selective for different enzyme-substrate complexes. Moreover, we showed that the molecular basis for this selectivity was a different association rate of the drug to a particular enzymatic form along the reaction pathway. By comparing the activities of the different compounds against wild-type RT and the nonnucleoside reverse transcriptase inhibitor-resistant mutant Lys103Asn, it was possible to hypothesize, on the basis of their mechanism of action, a rationale for the design of drugs which could overcome the steric barrier imposed by the Lys103Asn mutation.

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عنوان ژورنال:
  • Antimicrobial agents and chemotherapy

دوره 49 11  شماره 

صفحات  -

تاریخ انتشار 2005