2 research outputs found
Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family
17openPreventing HIV transmission by the use of a vaginal microbicide is a topic of considerable interest in the fight against AIDS. Both a potent anti-HIV agent and an efficient formulation are required to develop a successful microbicide. In this regard, molecules able to inhibit the HIV replication before the integration of the viral DNA into the genetic material of the host cells, such as entry inhibitors or reverse transcriptase inhibitors (RTIs), are ideal candidates for prevention purpose. Among RTIs, S- and N-dihydroalkyloxybenzyloxopyrimidines (S-DABOs and N-DABOs) are interesting compounds active at nanomolar concentration against wild type of RT and with a very interesting activity against RT mutations. Herein, novel N-DABOs were synthesized and tested as anti-HIV agents. Furthermore, their mode of binding was studied by molecular modeling. At the same time, a vaginal microbicide gel formulation was developed and tested for one of the most promising candidates.openTintori, Cristina; Brai, Annalaura; DASSO LANG, MARIA CHIARA; Deodato, Davide; Greco, Antonia Michela; Bizzarri, Bruno Mattia; Cascone, Lorena; Casian, Alexandru; Zamperini, Claudio; Dreassi, Elena; Crespan, Emmanuele; Maga, Giovanni; Vanham, Guido; Ceresola, Elisa; Canducci, Filippo; Ariën, Kevin K.; Botta, MaurizioTintori, Cristina; Brai, Annalaura; DASSO LANG, MARIA CHIARA; Deodato, Davide; Greco, Antonia Michela; Bizzarri, Bruno Mattia; Cascone, Lorena; Casian, Alexandru; Zamperini, Claudio; Dreassi, Elena; Crespan, Emmanuele; Maga, Giovanni; Vanham, Guido; Ceresola, Elisa; Canducci, Filippo; Ariën, Kevin K.; Botta, Maurizi
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Influenza
is an infectious disease that represents an important
public health burden, with high impact on the global morbidity, mortality,
and economy. The poor protection and the need of annual updating of
the anti-influenza vaccine, added to the rapid emergence of viral
strains resistant to current therapy make the need for antiviral drugs
with novel mechanisms of action compelling. In this regard, the viral
RNA polymerase is an attractive target that allows the design of selective
compounds with reduced risk of resistance. In previous studies we
showed that the inhibition of the polymerase acidic protein-basic
protein 1 (PA–PB1) interaction is a promising strategy for
the development of anti-influenza agents. Starting from the previously
identified 3-cyano-4,6-diphenyl-pyridines, we chemically modified
this scaffold and explored its structure–activity relationships.
Noncytotoxic compounds with both the ability of disrupting the PA–PB1
interaction and antiviral activity were identified, and their mechanism
of target binding was clarified with molecular modeling simulations