Carbonic anhydrase inhibitors: the beta-carbonic anhydrase from Helicobacter pylori is a new target for sulfonamide and sulfamate inhibitors.
DNA clones for the beta-class carbonic anhydrase (CA, EC 4.2.1.1) of Helicobactor pylori (hpbetaCA) were obtained. A recombinant hpbetaCA protein lacking the N-terminal 15-amino acid residues was produced and purified, representing a catalytically efficient CA. hpbetaCA was strongly inhibited (K(I)s in the range of 24-45 nM) by many sulfonamides/sulfamates, among which acetazolamide, ethoxzolamide, topiramate, and sulpiride, all clinically used drugs. The dual inhibition of alpha- and/or beta-class CAs of H. pylori might represent a useful alternative for the management of gastritis/gastric ulcers, as well as gastric cancer. This is also the first study showing that a bacterial beta-CA can be a drug target.
Nishimori
Isao
I
Department of Gastroenterology and Hepatology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
Minakuchi
Tomoko
T
Kohsaki
Takuhiro
T
Onishi
Saburo
S
Takeuchi
Hiroaki
H
Vullo
Daniela
D
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000595:Amino Acid Sequence; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003001:Cloning, Molecular; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D016480:Helicobacter pylori / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013274:Stomach Neoplasms / Q000188:drug therapy; D013276:Stomach Ulcer / Q000188:drug therapy; D013449:Sulfonamides / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D002257:Carbonic Anhydrase Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides; D002256:Carbonic Anhydrases