The natural product pateamine A (pateamine) from the sponge Mycale hentscheli is active against a wide range of dividing cells and has been shown to inhibit the functions of the eukaryotic initiation factor 4A (eIF4A). We have identified that pateamine is additionally able to modulate the formation of actin filaments and microtubules in vitro but at higher concentrations than required for inhibition of eIF4A. Cell cycle analysis confirmed that actin and tubulin are not major mediators of the cellular activity of pateamine. The range of targets identified demonstrates the value of multiple approaches to determining the mode of action of biologically active compounds.
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Immune Modulatory Profile of the Pateamines PatA and Des-Methyl Des-Amino PatA.
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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.
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Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, H3G 1Y6, Quebec, Canada.
Molecular staples or interfacial inhibitors are small molecules that exert their activity through co-association with macromolecules leading to various effects on target functions. Some molecules inhibit target activity, while others generate gain-of-function complexes. We and others have previously identified two structurally distinct classes of molecular staples, pateamine A and rocaglates.
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Small-molecule compounds that elicit mRNA-selective translation repression have attracted interest due to their potential for expansion of druggable space. However, only a limited number of examples have been reported to date. Here, we show that desmethyl desamino pateamine A (DMDA-PatA) represses translation in an mRNA-selective manner by clamping eIF4A, a DEAD-box RNA-binding protein, onto GNG motifs.
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RNA
June 2023
Department of Biochemistry, McGill University, Quebec, H3G 1Y6 Canada
Inhibition of eukaryotic translation initiation through unscheduled RNA clamping of the DEAD-box (DDX) RNA helicases eIF4A1 and eIF4A2 has been documented for pateamine A (PatA) and rocaglates-two structurally different classes of compounds that share overlapping binding sites on eIF4A. Clamping of eIF4A to RNA causes steric blocks that interfere with ribosome binding and scanning, rationalizing the potency of these molecules since not all eIF4A molecules need to be engaged to elicit a biological effect. In addition to targeting translation, PatA and analogs have also been shown to target the eIF4A homolog, eIF4A3-a helicase necessary for exon junction complex (EJC) formation.
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