| Autor: |
Cancio, Reynel, Silvestri, Romano, Ragno, Rino, Artico, Marino, De Martino, Gabriella, La Regina, Giuseppe, Crespan, Emmanuele, Zanoli, Samantha, Hübscher, Ulrich, Spadari, Silvio, Maga, Giovanni |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; November 2005, Vol. 49 Issue: 11 p4546-4554, 9p |
| Abstrakt: |
ABSTRACTIndolyl 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. |
| Databáze: |
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