Journal article

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

  • Cancio, Reynel Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy
  • Silvestri, Romano “Istituto Pasteur-Fondazione Cenci Bolognetti”-Dipartimento di Studi Farmaceutici, Università di Roma “La Sapienza,” P. le Aldo Moro 5, I-00185 Rome, Italy
  • Ragno, Rino “Istituto Pasteur-Fondazione Cenci Bolognetti”-Dipartimento di Studi Farmaceutici, Università di Roma “La Sapienza,” P. le Aldo Moro 5, I-00185 Rome, Italy
  • Artico, Marino “Istituto Pasteur-Fondazione Cenci Bolognetti”-Dipartimento di Studi Farmaceutici, Università di Roma “La Sapienza,” P. le Aldo Moro 5, I-00185 Rome, Italy
  • De Martino, Gabriella “Istituto Pasteur-Fondazione Cenci Bolognetti”-Dipartimento di Studi Farmaceutici, Università di Roma “La Sapienza,” P. le Aldo Moro 5, I-00185 Rome, Italy
  • La Regina, Giuseppe “Istituto Pasteur-Fondazione Cenci Bolognetti”-Dipartimento di Studi Farmaceutici, Università di Roma “La Sapienza,” P. le Aldo Moro 5, I-00185 Rome, Italy
  • Crespan, Emmanuele Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy
  • Zanoli, Samantha Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy
  • Hübscher, Ulrich Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich-Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
  • Spadari, Silvio Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy
  • Maga, Giovanni Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy
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Published in:
  • Antimicrobial Agents and Chemotherapy. - American Society for Microbiology. - 2005, vol. 49, no. 11, p. 4546-4554
English ABSTRACT
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.
Language
  • English
Open access status
bronze
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Persistent URL
https://sonar.ch/global/documents/160245
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