MGBG analogues as potent inhibitors of S-adenosylmethionine decarboxylase of Onchocerca volvulus

Polyamines are essential for cell growth and differentiation and therefore, S-adenosylmethionine decarboxylase (SAMDC), a key regulatory enzyme of the polyamine biosynthesis, is considered as a potentially important target for chemotherapy of filarial infections. Recombinant Onchocerca volvulus SAMDC was expressed in Escherichia coli and characterised. The enzyme activity was found to be stimulated 15-fold by addition of 1 mM putrescine. The K-m-value for S-adenosylmethionine was determined to be 36 mu M. Furthermore, the efficiencies of SAMDC inhibitors were analysed: Berenil inhibits the enzyme activity competitively with a K-i-value of 0.1 mu M. MDL 73811 acts as an irreversible inhibitor with a K-i-value of 1.4 mu M. Recently synthesised aromatic methylglyoxal bis(guanylhydrazone) analogues demonstrated high efficacy as inhibitors of the SAMDCs. Some of these analogues exhibited K-i-values of 5 and 14 nM for the Onchocerca enzyme, a result which shows an up to 100-fold increase in specificity compared to the value of 0.47 mu M for methylglyoxal bis(guanylhydrazone). These inhibitors might have potential as drug candidates against filarial worms. (C) 1998 Elsevier Science B.V. All rights reserved.