Inhibition of transcription factor NF-kappa B by sesquiterpene lactones: aproposed molecular mechanism of action

Many sesquiterpene lactones (SLs) possess considerable anti-inflammatory ac tivity. They inhibit the transcription factor NF-kappa B by selectively alk ylating its p65 subunit probably by reacting with cysteine residues. Here w e assayed 28 sesquiterpene lactones for their ability to inhibit NF-kappa B . The majority of the potent NF-kappa B inhibitors possess two reactive cen ters in form of an amethylene-gamma-lactone group and an alpha,beta- or alp ha,beta,gamma,delta-unsaturated carbonyl group. Based on computer molecular modelling we propose a molecular mechanism of action, which is able to exp lain the p65 selectivity of the SLs and the observed correlation of high ac tivity with alkylant bifunctionality. A single bifunctional SL molecule can alkylate the cysteine residue (Cys 38) in the DNA binding loop 1 (L1) and a further cysteine (Cys 120) in the nearby E' region. This cross link alter s the position of tyrosine 36 and additional amino acids in such a way that their specific interactions with the DNA become impossible. We also create d a model for monofunctional SLs. (C) 1999 Elsevier Science Ltd. All rights reserved.