Abstract
In this study, we isolated nine compounds from the acid hydrolysate of the flower buds of Lonicera fulvotomentosa Hsu et S. C. Cheng and characterized their chemical structures using 1H-NMR, 13C-NMR, and electron ionization mass spectroscopy (EI-MS). These compounds were identified as β-sitosterol (1), 5,5′-dibutoxy-2,2′-bifuran (2), nonacosane-10-ol (3), ethyl (3β)-3,23-dihydroxyolean-12-en-28-oate (4), oleanolic acid (5), ethyl caffeate (6), caffeic acid (7), isovanillin (8), and hederagenin (9), with 4 as a new triterpene compound. Inhibitory activity against human immunodeficiency virus (HIV) protease was also evaluated for the compounds, and only ethyl caffeate, caffeic acid, and isovanillin (6, 7, and 8) exhibited inhibitory effects, with IC50 values of 1.0 μM, 1.5 μM, and 3.5 μM, respectively. Molecular docking with energy minimization and subsequent molecular dynamic (MD) simulation showed that ethyl caffeate and caffeic acid bound to the active site of HIV protease, while isovanillin drifted out from the active site and dissociated into bulk water during MD simulations, and most of the binding residues of HIV protease have been previously identified for HIV protease inhibitors. These results suggest that caffeic acid derivatives may possess inhibitory activities towards HIV protease other than previously reported inhibitory activities against HIV integrase, and thus ethyl caffeate and caffeic acid could be used as lead compounds in developing potential HIV protease inhibitors, and possibly even dual-function inhibitors against HIV.
Highlights
Out of the nine compounds, ethyl caffeate and caffeic acid were identified to possess the highest inhibitory effects against human immunodeficiency virus (HIV) protease with respective IC50 values of 1.0 μM and 1.5 μM, suggesting that they could be used as lead compounds to develop more potent anti-HIV protease agents
Triterpene derivatives, caffeoylquinic acid derivatives, and flavonoids isolated from Lonicera species exhibit potent inhibitory effects against human immunodeficiency virus (HIV)-1 integrase and prevented HIV-1 replication in tissue culture [15,16,17,18,19]
There is evidence showing that strong binding to HIV-1 integrase does not always translate into potent antiviral activity [20,21]
Summary
Japonicae Flos (“Jin Yin Hua” in Chinese). Lonicera species have been shown to possess hepatoprotective, antiallergic, anti-inflammatory, antibacterial, and antiviral activities [6,7,8]. Various active ingredients, such as caffeoylquinic acid, secoiridoids, flavonoids, cerebrosides, nitrogen-containing iridoid glycosides, and triterpene glycosides, have been isolated and characterized from Lonicera species [9,10,11,12,13,14]. Cheng and evaluated their respective anti-HIV-protease activity under in vitro conditions, aiming to verify whether inhibition of HIV protease is involved in the anti-HIV function of Lonicera species. Out of the nine compounds, ethyl caffeate and caffeic acid were identified to possess the highest inhibitory effects against HIV protease with respective IC50 values of 1.0 μM and 1.5 μM, suggesting that they could be used as lead compounds to develop more potent anti-HIV protease agents
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