Organoselenium mild electrophiles in the inhibition of Mpro and SARSCoV-2 replication

Abstract

New Ebselen-like derivatives resulted to be very strong in vitro inhibitors of SARS-CoV-2 main protease. We demonstrated that this activity mainly depends on the electrophilicity of the selenium atom that is considerably higher in the N-substituted 1,2- benzoselenazol-3(2H)-ones respect to the corresponding diselenides allowing it to be rapidly attached by free thiols affording sulfur-selenium intermediates that are further subjected to thiol exchange processes. This data paints a very complex scenario that requires us to consider Ebselen and Ebselen-like derivatives as potential electrophilic substrates for the several other free thiols present in the cell beside the target free cysteine. The sulfur selenium intermediates are milder electrophiles that could be theoretically implicated in both the detoxification process as well as in the final enzymatic inhibition. We here demonstrated that the in vitro inhibition activity is not fully reproduced in the prevention of viral replication in the cell-based assay. This indicates that the structure of the substituents introduced in the Ebselen scaffold is a crucial factor to control the reactivity of the selenated molecule in the network of thiol exchanges, as well as for molecular recognition of the targeted enzymatic cysteine. For this reason, an in-depth investigation is strongly desirable to better understand how to increase the activity and the selectivity of Ebselen derivatives overcoming the issues of the apparent PAINS-like role of Ebselen. Furthermore, besides the antiviral activity, thee selected compounds also showed a different ability to reduce the virus-induced cytopathic effect, indicating that other mechanisms could be implicated. One may consider here the well-known cytoprotective antioxidant activity of Ebselen and its derivatives.<p></p>

Metal Complexes as Antiviral Agents for SARS‐CoV‐2

“…A handful of the compounds in this study were further tested in a cell assay. While Se2 was found to have an IC 50 value comparable to Ebselen, Se2 demonstrated a greater activity when compared to Ebselen in the cellular assay, suggesting that derivatization may be useful for obtaining more bioactive compounds in vivo [35] …”

Enantioselective inhibition of the SARS-CoV-2 main protease with rhenium(i) picolinic acid complexes

“…22 Based on these results, other studies have sought to optimize the activity of Ebselen toward SARS-CoV-2, but with limited success. [23][24][25] High-throughput screening studies by Ott et al and others have demonstrated that gold complexes could protect CaCo-2 cells from infections with SARS-CoV-2. 26 Alternatively, [Re(2,2 ′ -bipyridine)(CO) 3 (H 2 O)] + complexes were shown to act as coordinate covalent 3CL pro inhibitors.…”

Diphenyl Diselenide and SARS-CoV-2: in silico Exploration of the Mechanisms of Inhibition of Main Protease (Mpro) and Papain-like Protease (PLpro)

“…23 Of pharmacological significance, the plasmatic concentration of (PhSe) 2 after oral administration of relatively high doses to rodents is in the micromolar range. 7,23,37 In this work, after verifying the in vitro (PhSe) 2 effect against SARS-CoV-2 replication, we sought a possible mechanism of action through an in silico approach. For this purpose, we thoroughly analyze in silico the structural and chemical mechanism of SARS-CoV-2 proteases' inhibition by (PhSe) 2 , employing molecular docking, molecular dynamics (MD), and density functional theory (DFT) protocols.…”