Cloning, characterization, and sulfonamide and thiol inhibition studies of an α-carbonic anhydrase from Trypanosoma cruzi, the causative agent of Chagas disease

Peiwen Pan; Alane Beatriz Vermelho; Giseli Capaci Rodrigues; Andrea Scozzafava; Martti E E Tolvanen; Seppo Parkkila; Clemente Capasso; Claudiu T Supuran

doi:10.1021/jm4000616

Cloning, characterization, and sulfonamide and thiol inhibition studies of an α-carbonic anhydrase from Trypanosoma cruzi, the causative agent of Chagas disease

J Med Chem. 2013 Feb 28;56(4):1761-71. doi: 10.1021/jm4000616. Epub 2013 Feb 19.

Authors

Peiwen Pan¹, Alane Beatriz Vermelho, Giseli Capaci Rodrigues, Andrea Scozzafava, Martti E E Tolvanen, Seppo Parkkila, Clemente Capasso, Claudiu T Supuran

Affiliation

¹ Institute of Biomedical Technology, Fimlab Ltd., School of Medicine and BioMediTech, University of Tampere and Tampere University Hospital, Medisiinarinkatu 3, 33520 Tampere, Finland.

PMID: 23391336
DOI: 10.1021/jm4000616

Abstract

An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry*
Carbonic Anhydrase Inhibitors / pharmacology
Carbonic Anhydrases / chemistry
Carbonic Anhydrases / genetics*
Chagas Disease / parasitology
Cloning, Molecular
Humans
Molecular Sequence Data
Phylogeny
Protozoan Proteins / antagonists & inhibitors
Protozoan Proteins / chemistry
Protozoan Proteins / genetics*
Structure-Activity Relationship
Sulfhydryl Compounds / chemical synthesis
Sulfhydryl Compounds / chemistry*
Sulfhydryl Compounds / pharmacology
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / pharmacology
Thiadiazoles / chemical synthesis
Thiadiazoles / chemistry*
Thiadiazoles / pharmacology
Trypanocidal Agents / chemical synthesis
Trypanocidal Agents / chemistry*
Trypanocidal Agents / pharmacology
Trypanosoma cruzi / drug effects
Trypanosoma cruzi / enzymology*

Substances

Carbonic Anhydrase Inhibitors
Protozoan Proteins
Sulfhydryl Compounds
Sulfonamides
Thiadiazoles
Trypanocidal Agents
Carbonic Anhydrases