Immune Modulatory Profile of the Pateamines PatA and Des-Methyl Des-Amino PatA.

Pateamines act as inhibitors of the RNA helicase eIF4A and exhibit antiviral and anticancer properties. Recently, we observed that inhibition of eIF4A by rocaglates affects the immune response. To investigate whether the observed immunomodulatory effects are specific to rocaglates or the inhibition of eIF4A, a comprehensive study was conducted on the influence of pateamines that exhibit the same inhibitory mode of action as rocaglates on various immune cells. The effects of pateamine A (PatA) and des-methyl des-amino pateamine A (DMDA) on the expression of surface markers, release of cytokines, cell proliferation, inflammatory mediators and metabolic activity in primary human monocyte-derived macrophages (MdM), T cells and B cells were assessed. Additionally, safety and bioavailability profiles were determined. DMDA revealed almost no immunomodulatory effects within the tested concentration range of 0.5-5 nM. PatA reduced B cell activation, as shown by reduced immune globulin release and decreased chemokine release from macrophages, while T cell function remained unaffected. Both DMDA and PatA showed low permeability in Caco-2 and Calu-3 cell barrier assays and no mutagenic potential. However, 10 nM PatA exhibited genotoxic potential, as shown by the micronucleus assay. In conclusion, DMDA had a good safety profile but exhibited low permeability, whereas PatA had a poor safety profile and also low permeability. The observed immunomodulatory effects of elF4A inhibitors on B cells appear to be target-specific.