Download The fight against AIDS: new avenues for inhibiting Reverse

The fight against AIDS: new avenues for inhibiting Reverse Transcriptase
(RT), an old target
Maurizio Botta
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de
Gasperi 2, I-53100, Siena, Italy, [email protected]
Abstract
The Acquired Immunodeficiency Syndrome (AIDS) related to HIV-1 infection is one
of the most serious threats to human health and it has been estimated that more than 25
million people were killed since it was first recognized. In the fight against AIDS, first and
second generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) are now
established as part of highly active antiretroviral therapy (HAART) for treating HIV
infection. However, the efficacy of currently available NNRTIs, e.g. nevirapine (NVP,
Viramune®), delavirdine (DLV, Rescriptor®) and efavirenz (EFV, Sustiva®, Stocrin®), is
impaired by rapid emergence of drug resistance. On the other hand, as patients live longer on
HAART therapy and the pool of NNRTI-resistant viruses increases, so does the need for the
development of new NNRTIs with antiviral activity against clinically relevant mutant strains.
Our research group has been recently involved in a multi-target approach to defeat the HIVvirus, focusing on the inhibition of HIV-1 Reverse Transcriptase according to both classical
and non-classical approaches.
Here it will be reported an efficient methodology for the parallel solution-phase
synthesis of a series of thiouracils, in turn selectively S-benzylated under microwave
irradiation to give new S-DABOs. S-DABO derivatives, endowed with subnanomolar antiHIV-1 activity, were subjected to docking and molecular dynamic studies, with the aim to
rationalize their activity both within the wt:RT and K103N:RT non-nucleoside binding
pocket (NNBP).
A combinatorial approach, lead instead to the identification of a new class of
compounds (namely 6-vinylpyrimidines) endowed with an unprecedent mechanism of action:
these compounds resulted in fact to be the first non-nucleoside RT inhibitors (NNRTIs)
competing with the nucleotide substrate. An enzymological and computational study has been
conducted to elucidate their unique mechanism of action.
Acknowledgment: Fabrizio Manetti, Lucilla Angeli, Luca Bellucci, Marco Radi, Maddalena
Alongi, Claudia Mugnaini, Federico Corelli, Silvio Massa, Giovanni Maga, José A. Esté.