Abstract
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme involved in the Trypanosoma cruzi glycolytic pathway, parasite that causes Chagas' disease. There are only few drugs available to treat this disease, most of which present strong side effects. Natural products constitute a prime source for the discovery of new scaffolds potentially useful for the treatment of several diseases, including Chagas' disease. Bioactivity-guided fractionation of Spiranthera odoratissima extract using T. cruzi GAPDH (TcGAPDH) as a target led to the isolation of the flavonoid tiliroside (kaempferol-3-O-β-D-(6''-trans-p-coumaroyl)-glucopyranoside), identified as an excelent inhibitor of this enzyme and for the first time reported for this plant species. Mechanistic studies of tiliroside showed that it is a reversible non-competitive inhibitor of TcGAPDH. In additon, molecular modeling analysis indicated the binding mode of tiliroside to TcGAPDH. Therefore, the identification of tiliroside as TcGPADH inhibitor in a complex matrix such as the plant crude extract and the discovery of a new binding site may contribute to the opening of new paths in the search for natural product inhibitors of this enzyme.
Highlights
In 1909 the Brazilian physician Carlos Chagas first described the disease that bears his name.[1]
Extracts from several species from Rutaceae family were evaluated against T. cruzi GAPDH (TcGAPDH), Spiranthera odoratissima ethanolic crude extract (SOGE) showed the most promising results, with inhibition higher than 60% at a concentration of 200 μg mL-1 (Figure S1)
Phytochemical study and subsequent fractioning of the EtOAc extract led to the isolation of active known compound kaempferol-3-O-β-D-(6’’-trans-p-coumaroyl)glucopyranoside (Figure 2), for first time reported in Spiranthera odoratissima
Summary
In 1909 the Brazilian physician Carlos Chagas first described the disease that bears his name.[1]. As S. odoratissima presented the most promising inhibition, bioactivity-guided fractionation of the crude ethanolic extract from the stems (27.0 g) was initiated by liquid-liquid partition into hexane (3.5 g), CH2Cl2 (4.0 g), EtOAc (2.5 g) and hydroalcoholic (15.0 g) extracts, only EtOAc and hydroalcoholic extracts showed significant inhibitory activity against TcGAPDH (Figure S2).
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