np9b00649_si_001.pdf (2.16 MB)
Oleanolic Acid Derivatives as Potential Inhibitors of HIV‑1 Protease
journal contribution
posted on 2019-10-15, 20:45 authored by Marta Medina-O’Donnell, Francisco Rivas, Fernando J. Reyes-Zurita, Mario Cano-Muñoz, Antonio Martinez, Jose A. Lupiañez, Andres ParraPentacyclic triterpenes, such as
oleanolic acid (I), are promising scaffolds for diversification
through the use of
combinatorial methods to obtain derivatives that improve their biological
properties, increasing their bioavailability and enhancing their therapeutic
efficacy. The purpose of this study was to evaluate the influence
that derivatives of oleanolic acid, conjugated with one or two amino
acids and an acyl group, might exert on HIV-1 protease inhibition.
The in vitro studies conducted suggested that the presence of a carboxyacyl
group generally improves the inhibition of HIV-1 protease, especially
when a phthaloyl group is present, with IC50 concentration
values below 5 μM. The gain in activity of three 3-phthaloyl
derivatives, with sub-micromolar IC50 values, was between
60- and 100-fold more active than oleanolic acid. A molecular docking
study has also been performed to elucidate the mode of binding to
the protease by these oleanolic acid derivatives. In general, the
derivatives that exhibited the highest inhibitory activity of HIV-1
protease also showed the highest binding energies in docking simulations.
The overall results suggest that the coupling of one or two amino
acids and a phthaloyl group to oleanolic acid improves HIV-1 protease
inhibition, implying that these triterpene derivatives may be promising
antiviral agents against HIV.