ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A

Abstract

Activation of translation initiation is a common trait of cancer cells. Formation of the heterotrimeric eukaryotic initiation factor F (eIF4F) complex is the rate-limiting step in 5′ m7GpppN cap-dependent translation. This trimeric complex includes the eIF4E cap binding protein, the eIF4G scaffolding protein, and the DEAD box RNA helicase eIF4A. eIF4A is an ATP-dependent helicase and because it is the only enzyme in the eIF4F complex, it has been shown to be a potential therapeutic target for a variety of malignancies. To this end, we have used a simple ATPase biochemical screen to survey several hundred marine and terrestrial derived natural products. Herein, we report the discovery of two natural products from marine sources, elisabatin A (1) and allolaurinterol (2), which show low µM inhibition of eIF4A ATPase activity. Enzymological analyses revealed 1 and 2 to be ATP-competitive, and cellular evaluations showed reasonable cytotoxicity against A549 (lung cancer) and MDA-MA-468 (breast cancer) cell lines. However, only compound 2 showed potent inhibition of helicase activity congruent with its ATPase inhibitory activity.

Laurinterol from Laurencia johnstonii eliminates Naegleria fowleri triggering PCD by inhibition of ATPases

“…The compound also showed potent inhibition of helicase activity consistent with its ATPase inhibitory activity with complete inhibition at 100 µM. Thus, this data proved that allolaurienterol is an ATP-competitive molecule most likely binding to the ATP-binding pocket at the interface between the N-terminal and C-terminal domains 38,39 .…”

“…This assumption is based on the fact that laurinterol dimer ( 5 ) (Fig. 13 ) does not show activity (IC 50 > 100 µM), possibly due to the increasement in volume of the molecule, which may limit the capacity to interact with the ATPases nucleotide binding pocket 38 , 39 , 43 . Nevertheless, further studies to evaluate this drug target as well as SARs approaches should be developed in the near future.…”

Eukaryotic initiation factor 4A (eIF4A) during viral infections

“…There are some compounds that have the characteristic of inhibiting eIF4A: silvestrol [59], hippuristanol [60], elisabatin and allolaurintenol [61], rocaglamide [62], and pateamine A and some of its derivatives [30]. These compounds are emerging as a new antiviral therapeutic strategy whose mechanism of action is the inhibition of eIF4A.…”

Molecular Targets of Active Anticancer Compounds Derived from Marine Sources

“…DEAD box RNA helicase eIF4A is an ATP-dependent helicase involved in RNA metabolism. It is a potential therapeutic target for a variety of malignancies [ 84 ]. Tillotson et al [ 84 ] reported that marine-derived natural products such as elisabatin A (No.…”