Ebola Entry Inhibitors Discovered from Maesa perlarius

Abstract

Ebola virus disease (EVD), a disease caused by infection with Ebola virus (EBOV), is characterized by hemorrhagic fever and a high case fatality rate. With limited options for the treatment of EVD, anti-Ebola viral therapeutics need to be urgently developed. In this study, over 500 extracts of medicinal plants collected in the Lingnan region were tested against infection with Ebola-virus-pseudotyped particles (EBOVpp), leading to the discovery of Maesa perlarius as an anti-EBOV plant lead. The methanol extract (MPBE) of the stems of this plant showed an inhibitory effect against EBOVpp, with an IC50 value of 0.52 µg/mL, which was confirmed by testing the extract against infectious EBOV in a biosafety level 4 laboratory. The bioassay-guided fractionation of MPBE resulted in three proanthocyanidins (procyanidin B2 (1), procyanidin C1 (2), and epicatechin-(4β→8)-epicatechin-(4β→8)-epicatechin-(4β→8)-epicatechin (3)), along with two flavan-3-ols ((+)-catechin (4) and (−)-epicatechin (5)). The IC50 values of the compounds against pseudovirion-bearing EBOV-GP ranged from 0.83 to 36.0 µM, with 1 as the most potent inhibitor. The anti-EBOV activities of five synthetic derivatives together with six commercially available analogues, including EGCG ((−)-epigallocatechin-3-O-gallate (8)), were further investigated. Molecular docking analysis and binding affinity measurement suggested the EBOV glycoprotein could be a potential molecular target for 1 and its related compounds.

Tackling the Future Pandemics: Broad-Spectrum Antiviral Agents (BSAAs) Based on A-Type Proanthocyanidins

“…Dimeric PAC and several flavan-3-ol monomers within this extract were found to be potent EBOV entry inhibitors at low micromolar concentrations. By docking analysis and microscale thermophoresis technology, the authors determined that these compounds exhibited virucidal potency by interacting with EBOV glycoprotein, and the most efficient antiviral compound was the PAC-B2 [ 259 ].…”

Procyanidin C1 Location, Interaction, and Aggregation in Two Complex Biomembranes

“…The bioactive procyanidins are known for their ample benefits to human health and have been shown to have a plethora of biological effects [ 3 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. The bioactive effects of procyanidins in general, PC1 in particular, could be ascribed to their capability to localize in the biological membrane and to modulate the membrane structure and/or the dynamics, as well as their interaction with the lipids and proteins [ 23 ].…”

“…Interestingly, the quantity of procyanidins is very high in vegetables, fruits, cereals, and the seeds of numerous species of plants [ 2 , 4 ] and they are very heterogeneous compounds with a diverse chemical structure [ 5 , 6 ]. Most importantly, they have been shown to possess a plethora of valuable properties, which include anticarcinogenic, antimicrobial, antiviral, antiinflammatory, antiallergic, antimutagenic, and antihyperglycaemic effects [ 3 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

N-Substituted Pyrrole-Based Heterocycles as Broad-Spectrum Filoviral Entry Inhibitors

“…1 H NMR (400 MHz, CD 3 OD) δ 7.59− 7.55 (m, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.32 (dt, J = 8.4, 1.5 Hz, 1H), 6.84 (d, J = 1.0 Hz, 1H), 6.52 (dd, J = 2.3, 0.9 Hz, 1H), 5.78 (s, 2H). (34). To a solution of 4g (46.5 mg, 135 μmol) in dry DMF (3.00 mL/mmol) cooled to 0 °C, DIPEA (5.00 equiv, 676 μmol) and HATU (2.00 equiv, 271 μmol) were added sequentially.…”

“…More work is needed for small molecules that target entry. Structure−activity relationship studies have identified benzamides, 32 adamantane carboxamides, 33 and proanthocyanidins 34 that display potent activity against EBOV; however, additional characterization against other filoviruses has not been reported. In contrast, a ridaifen-B analogue, XL-147, displayed favorable broad-spectrum antifiloviral activity, yet off-target effects at the estrogen receptor need to be addressed before further advancement.…”