Selective targeting of the HIV-1 reverse transcriptase catalytic complex through interaction with the (Articolo in rivista)

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  • Selective targeting of the HIV-1 reverse transcriptase catalytic complex through interaction with the (Articolo in rivista) (literal)
Anno
  • 2008-01-01T00:00:00+01:00 (literal)
Alternative label
  • Zanoli S, Gemma S, Butini S, Brindisi M, Joshi BP, Campiani G, Fattorusso C, Persico M, Crespan E, Cancio R, Spadari S, Hübscher U, Maga G. (2008)
    Selective targeting of the HIV-1 reverse transcriptase catalytic complex through interaction with the
    in Biochemical pharmacology
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Zanoli S, Gemma S, Butini S, Brindisi M, Joshi BP, Campiani G, Fattorusso C, Persico M, Crespan E, Cancio R, Spadari S, Hübscher U, Maga G. (literal)
Pagina inizio
  • 156 (literal)
Pagina fine
  • 168 (literal)
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  • 76 (literal)
Rivista
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  • full paper (literal)
Note
  • ISI Web of Science (WOS) (literal)
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  • Institute of Molecular Genetics, IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy; Dipartimento Farmaco Chimico Tecnologico, Universita’ degli Studi di Siena, via Aldo Moro, I-53100 Siena, Italy; Dipartimento di Chimica delle Sostanze Naturali, Universita' di Napoli \"Federico II\", via D. Montesano 49, I-80131 Napoli, Italy; Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich-Irchel, CH-8057 Zürich, Switzerland; European Research Centre for Drug Discovery and Development, Universita' degli Studi di Siena, I-53100 Siena, Italy (literal)
Titolo
  • Selective targeting of the HIV-1 reverse transcriptase catalytic complex through interaction with the (literal)
Abstract
  • PBO (pyrrolobenzoxazepinone) derivatives are non-nucleoside reverse transcriptase inhibitors (NNRTIs), which display a selective interaction with the catalytic ternary complex of HIV-1 reverse transcriptase (RT) and its substrates. In order to develop novel PBOs with improved resistance profiles, we synthesised additional PBO derivatives, specifically designed to target highly conserved residues in the beta12-beta13 hairpin, the so-called \"primer grip\" region of HIV-1 RT. Here, we investigated the biochemical and enzymological mechanism of inhibition of HIV-1 RT wild type and carrying NNRTIs-resistance mutations, by these derivatives. Our kinetic analysis indicates that the ability of PBOs to selectively target the catalytic ternary complex of RT with its substrates directly correlates with greatly reduced sensitivity to NNRTIs-resistance mutations, particularly the K103N substitution. Molecular modeling and docking studies provided an explanation for this correlation at the structural level. (literal)
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