Background: Novel indolylarylsulfones (IASs), designed through rational structure-based molecular modelling and docking approaches, have been recently characterized as effective inhibitors of the wild-type and drug-resistant mutant HIV-1 reverse transcriptase (RT). Methods: Here, we studied the interaction of selected halo- and nitro-substituted IAS derivatives, with the RT enzyme carrying the single resistance mutations K103N and Y181I through steady-state kinetic experiments. Results: The studied compounds exhibited high selectivity to the mutant RT in complex with its substrates, behaving as uncompetitive inhibitors. The presence of the K103N mutation, and to a lesser extent the Y181I, stabilized the drug interactions with the viral RT, when both its substrates were bound. Conclusions: The characterization of these mutation-specific effects on inhibitor binding might be relevant to the design of more effective new generation non-nucleoside reverse transcriptase inhibitors, with better resilience towards drug resistant mutants.

Mechanism of interaction of novel indolylarylsulfone derivatives with K103N and Y181I mutant HIV-1 reverse transcriptase in complex with its substrates / A., Samuele; S., Bisi; A., Kataropoulou; LA REGINA, Giuseppe; Piscitelli, Francesco; Gatti, Valerio; Silvestri, Romano; G., Maga. - In: ANTIVIRAL CHEMISTRY & CHEMOTHERAPY. - ISSN 0956-3202. - 22(2011), pp. 107-118. [10.3851/IMP1855]

Mechanism of interaction of novel indolylarylsulfone derivatives with K103N and Y181I mutant HIV-1 reverse transcriptase in complex with its substrates

LA REGINA, GIUSEPPE;PISCITELLI, FRANCESCO;GATTI, VALERIO;SILVESTRI, Romano;
2011

Abstract

Background: Novel indolylarylsulfones (IASs), designed through rational structure-based molecular modelling and docking approaches, have been recently characterized as effective inhibitors of the wild-type and drug-resistant mutant HIV-1 reverse transcriptase (RT). Methods: Here, we studied the interaction of selected halo- and nitro-substituted IAS derivatives, with the RT enzyme carrying the single resistance mutations K103N and Y181I through steady-state kinetic experiments. Results: The studied compounds exhibited high selectivity to the mutant RT in complex with its substrates, behaving as uncompetitive inhibitors. The presence of the K103N mutation, and to a lesser extent the Y181I, stabilized the drug interactions with the viral RT, when both its substrates were bound. Conclusions: The characterization of these mutation-specific effects on inhibitor binding might be relevant to the design of more effective new generation non-nucleoside reverse transcriptase inhibitors, with better resilience towards drug resistant mutants.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11573/502211
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