Discovery and structural optimization of 3-O-β-chacotriosyl oleanane-type triterpenoids as potent entry inhibitors of SARS-CoV-2 virus infections

Abstract

Currently, SARS-CoV-2 virus is an emerging pathogen that has posed a serious threat to public health worldwide. However, no agents have been approved to treat SARS-CoV-2 infections to date, underscoring the great need for effective and practical therapies for SARS-CoV-2 outbreaks. We reported that a focused screen of OA saponins identified 3- O -β-chacotriosyl OA benzyl ester 2 as a novel small molecule inhibitor of SARS-CoV-2 virus entry, via binding to SARS-CoV-2 glycoprotein (S). We performed structure-activity relationship profiling of 2 and discovered C-17-COOH of OA was an important modification site that improved both inhibitor potency toward SARS-CoV-2 and selectivity index. Then optimization from hit to lead resulted in a potent fusion inhibitor 12f displaying strong inhibition against infectious SARS-CoV-2 with an IC 50 value of 0.97 μM in vitro . Mechanism studies confirmed that inhibition of SARS-CoV-2 viral entry of 12f was mediated by the direct interaction with SARS-CoV-2 S2 subunit to block membrane fusion. These 3- O -β-chacotriosyl OA amide saponins are suitable for further optimization as SARS-CoV-2 entry inhibitors with the potential to be developed as therapeutic agents for the treatment of SARS-CoV-2 virus infections.

Modeling the Structure–Activity Relationship of Arbidol Derivatives and Other SARS-CoV-2 Fusion Inhibitors Targeting the S2 Segment of the Spike Protein

“…To our knowledge, this is the first literature report of a specific compound binding to the S2 segment. 54 According to our pharmacophore map and subsequent molecular docking results using that map, this series of OA saponin fusion inhibitors are predicted to bind to the S2 segment at our predicted Site 1 ( Figure 11 ).…”

“… Predicted Δ G bind values from Site 1 exhibit correlation with experimental SAR data. (A) Series of OA saponin derivatives 54 were well modeled binding to Site 1, where sufficient linear correlation is achieved either comparing (B) all 14 derivatives (blue) or (C) 14 OA saponin derivatives modeled as two separate groups of linear series 1 (blue) or series 2 (red). (D) Predicted Δ G bind values for all 14 compound modeled at Site 2 exhibit lower correlation ( R 2 = 0.097).…”

“…To better understand the structural implications of the experimental data from ARB derivatives, this study was extended to a series of oleanolic acid (OA) trisaccharide saponin derivatives 54 that are fusion inhibitors shown to directly bind to the S2 segment by a biophysical surface plasmon resonance (SPR) binding assay. OA saponin derivative 12a was selected as a reference molecule to dock to all 50 sites, as it had one less flexible degree of freedom in the R-group in comparison to 12f .…”

“…As there was good agreement (RMSD < 2.0 Å) between the top-ranked geometries of saponin 12a (without trisaccharide) initiated from 10 random conformations and saponin 12a (with trisaccharide) initiated from 40 random conformations at the TOP2 ranked sites, docking studies were initiated from 10 random conformations of saponin derivatives (without trisaccharide) to compare to experimental activity data. OA saponin derivatives 54 ( 12a , 12b , 12c , 12d , 12e , 12f , 12i , 12j , 12k , 12l , 12m , 12n , 12o , and 12p ) were modeled in this way at the TOP2 binding sites on the S2 segment where the calculated Δ G bind values are analyzed for correlation with experimental log IC50 values. Pearson’s R and ( R 2 ) values are calculated as well as root-mean-squared error (RMSE).…”

Antcins from Antrodia cinnamomea and Antrodia salmonea Inhibit Angiotensin-Converting Enzyme 2 (ACE2) in Epithelial Cells: Can Be Potential Candidates for the Development of SARS-CoV-2 Prophylactic Agents

“…Additionally, oleanolic acid and glycyrrhetinic acid have been proven effective in reducing the spike RBD’s adhesion to its ACE2 consensus in vitro. The structural optimization study with 3- O -chacotriosyl oleanane-type triterpenoid inhibits SARS-CoV-2 virus entry via binding to SARS-CoV-2 glycoprotein (S) [ 28 ]. In addition, structurally similar synthetic corticosteroids such as dexamethasone exert anti-inflammatory effects and are prescribed medicines for critically ill COVID-19 patients.…”