Characterisation of the RNA helicase eIF4A as potential drug target against Schistosoma mansoni

The eukaryotic initiation factor 4A (eIF4A) is a DEAD-box RNA helicase that unwinds secondary structures in the 5’ untranslated region (UTR) of mRNAs in the presence of ATP. This enables binding of the preinitiation complex and subsequently protein synthesis1.  

In this project, two eIF4A helicases of Schistosoma mansoni (SmeIF4A) will be analysed molecularly and biochemically. For this purpose, both genes are cloned and recombinantly expressed in Escherichia coli. The enzymes will be further characterised by activity assays, and their potential inhibition by known eIF4A inhibitors will be screened.  

 Fig. 1: Function of the RNA helicase eIF4A and its inhibition by rocaglates.  

eIF4A unwinds secondary structures in the 5’ UTRs of mature mRNAs.

This enables ribosome binding and thus protein synthesis.

Compounds isolated from plants of the genus Aglaia inhibit eIF4A specifically.  

1 Parsyan A, Svitkin Y, Shahbazian D, Gkogkas C, Lasko P, Merrick WC, Sonenberg N (2011).    mRNA helicases: the tacticians of translational control. Nat Rev Mol Cell Biol. 12(4): 235-45.  

2 Bordeleau ME, Robert F, Gerard B, Lindqvist L, Chen SMH, Wendel HG, Brem B, Greger H, Lowe SW, Porco JA Jr, Pelletier J (2008). Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 118(7):2651-60. 

3 Müller C, Schulte FW, Lange-Grünweller K, Obermann W, Madhugiri R, Pleschka S, Ziebuhr J, Hartmann RK, Grünweller A (2018). Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses. Antiviral Res. 150:123-129 

4 Hwang BY, Su BN, Chai H, Mi Q, Kardono LB, Afriastini JJ, Riswan S, Santarsiero BD, Mesecar AD, Wild R, Fairchild CR, Vite GD, Rose WC, Farnsworth NR, Cordell GA, Pezzuto JM, Swanson SM, Kinghorn AD (2004). Silvestrol and episilvestrol, potential anticancer rocaglate derivatives from Aglaia silvestris. J Org Chem. 69(10):3350-8.