mdl-73811 and diminazene-aceturate

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 Km-value for S-adenosylmethionine was determined to be 36 microM. Furthermore, the efficiencies of SAMDC inhibitors were analysed: Berenil inhibits the enzyme activity competitively with a Ki-value of 0.1 microM. MDL 73811 acts as an irreversible inhibitor with a Ki-value of 1.4 microM. Recently synthesised aromatic methylglyoxal bis(guanylhydrazone) analogues demonstrated high efficacy as inhibitors of the SAMDCs. Some of these analogues exhibited Ki-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 microM for methylglyoxal bis(guanylhydrazone). These inhibitors might have potential as drug candidates against filarial worms.

Topics: Adenosylmethionine Decarboxylase; Animals; Cloning, Molecular; Deoxyadenosines; Diminazene; Enzyme Inhibitors; Escherichia coli; Filaricides; Filarioidea; Genetic Vectors; Helminth Proteins; Humans; Mitoguazone; Onchocerca volvulus; Organic Chemicals; Polyamines; Recombinant Proteins