Paper Citing NAMD - Abstract
Botta, Maurizio; Angeli, Lucilla; Radi, Marco; Maga, Giovanni
The fight against AlDS: New avenues for inhibiting reverse transcriptase (RT), an old target
Chemistry and Molecular Aspects of Drug Design and Action, 325-346, 2008
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 have died 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 (R)), delavirdine (DLV, Rescriptor (R)), and efavirenz (EFV, Sustiva (R), Stocrin (R)), 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 was recently involved in a multitarget approach to defeat the HIV virus, focusing on the inhibition of HIV-1 reverse transcriptase according to both classical and nonclassical approaches.Here, we will report an efficient methodology for the parallel solution-phase synthesis of a series of thiouracils, in turn selectively S-benzylated under microwave irradiation to give Dew S-DABOs. S-DABO derivatives, endowed with subnanomolar anti-HIV-1 activity, were subjected to docking and molecular dynamic studies, with the aim of rationalizing their activity both within the wild-type:RT and K103N: RT nonnucleoside binding pocket (NNBP).A combinatorial approach led instead to the identification of a new class of compounds (namely 6-vinylpyrimidines) endowed with an unprecedented mechanism of action: these compounds are the first NNRTIs competing with the nucleotide substrate. An enzymological and computational study has been conducted to elucidate their unique mechanism of action.
