In Vitro Safety, Off-Target and Bioavailability Profile of the Antiviral Compound Silvestrol

Abstract

We characterized the in vitro safety and bioavailability profile of silvestrol, a compound effective against various viruses, such as corona- and Ebolaviruses, with an EC50 value of about 5 nM. The cytotoxic profile of silvestrol was assessed in various cancer cell lines, as well as the mutagenic and genotoxic potential with Ames and micronuclei tests, respectively. To identify off-target effects, we investigated whether silvestrol modulates G-protein coupled receptor (GPCR) signaling pathways. To predict the bioavailability of silvestrol, its stability, permeability and cellular uptake were determined. Silvestrol reduced viability in a cell-type-dependent manner, mediated no off-target effects via GPCRs, had no mutagenic potential and minor genotoxic effects at 50 nM. Silvestrol did not disturb cell barrier integrity, showed low membrane permeability, was stable in liver microsomes and exhibited good cellular uptake. Efficient cellular uptake and increased cytotoxicity were observed in cell lines with a low expression level of the transport protein P-glycoprotein, the known efflux transporter of silvestrol. In conclusion, silvestrol showed low permeability but good cellular uptake and high stability. Cell-type-dependent cytotoxicity seems to be caused by the accumulation of silvestrol in cells lacking the ability to expel silvestrol due to low P-glycoprotein levels.

Comparing the Effects of Rocaglates on Energy Metabolism and Immune Modulation on Cells of the Human Immune System

“…Activation of NF-AT proceeds via IP 3 , calcium release and activation of calcineurin, which dephosphorylates NF-AT at serine residues, initiating its translocation to the nucleus [ 34 ]. Since NF-AT-dependent cytokines were downregulated in T cells, it is possible that the rocaglates investigated here also interfere with the NF-AT signaling pathway, but we could not detect IP 3 or Ca 2+ release in the presence of silvestrol in HEK293T cells [ 35 ]. Proksch et al, also failed to observe Ca 2+ induction in Jurkat T cells with rocaglates [ 33 ].…”

Targeting EBV‐encoded products: Implications for drug development in EBV‐associated diseases

“…Additionally, due to its low bioavailability, the oral administration of Silvesterol should be avoided in clinical applications, while topical administration is preferred. 37 Resveratrol can interfere with cell differentiation and inhibit apoptosis by suppressing the activity of STAT3 (Figure 1). Additionally, resveratrol can also inhibit its subsequent pathways by downregulating LMP1.…”

“… 36 It has been suggested that Silvesterol may exhibit mild genotoxicity at higher concentrations, and it is important to further investigate and address these potential side effects. Additionally, due to its low bioavailability, the oral administration of Silvesterol should be avoided in clinical applications, while topical administration is preferred 37 …”