title: MGBG analogues as potent inhibitors of S-adenosylmethionine decarboxylase of Onchocerca volvulus.
abstract: 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.
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine, Department of Biochemistry, Hamburg, Germany.
authors.forename: A A
authors.initials: AA
authors.lastname: Da'dara
authors.forename: H
authors.initials: H
authors.lastname: Mett
authors.forename: R D
authors.initials: RD
authors.lastname: Walter
mesh_terms: D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003001:Cloning, Molecular / Q000379:methods; D003839:Deoxyadenosines / Q000494:pharmacology; D004133:Diminazene / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D005369:Filaricides / Q000494:pharmacology; D005370:Filarioidea / Q000187:drug effects; D005822:Genetic Vectors; D015801:Helminth Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008935:Mitoguazone / Q000494:pharmacology*; D017181:Onchocerca volvulus / Q000201:enzymology*; D009930:Organic Chemicals; D011073:Polyamines / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis
chemical_list: D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D005369:Filaricides; D015801:Helminth Proteins; C112284:MDL 73815; D009930:Organic Chemicals; D011073:Polyamines; D011994:Recombinant Proteins; C065859:MDL 73811; D012437:Adenosylmethionine Decarboxylase; C003915:diminazene aceturate; D008935:Mitoguazone; D004133:Diminazene